Kaoru Kahata

Progressive disappearance of anti-hepatitis B surface antigen antibody and reverse seroconversion after allogeneic hematopoietic stem cell transplantation in patients with previous hepatitis B virus infection

Reactivation of resolved hepatitis B virus (HBV) infection, which is known as reverse seroconversion (RS), has been reported as a rare complication of allogeneic hematopoietic stem cell transplantation. We retrospectively studied HBV serologic markers in 14 recipients with pretransplant anti-hepatitis B surface antigen antibody (anti-HBs). Progressive decreases in anti-HBs titer were observed in all cases. In 12 cases, anti-HBs titer had decreased to under the protective value. RS occurred in seven cases after disappearance of anti-HBs. Although reseroconversion occurred in five cases, two cases remained in an HBV-carrier status after resolution of hepatitis. In the other five cases, RS did not occur even after disappearance of anti-HBs. The actual risks of anti-HBs disappearance and RS were estimated to be 75.0% and 39.8% at 2 years and 100.0% and 70.0% at 5 years, respectively. In conclusion, RS is a late-onset complication with high frequency that can be predicted by careful monitoring of progressive decrease in anti-HBs titer.

A Retrospective Analysis of Allogeneic Hematopoietic Stem Cell Transplantation for Adult T Cell Leukemia/Lymphoma (ATL): Clinical Impact of Graft-versus-Leukemia/Lymphoma Effect

Adult T cell leukemia/lymphoma (ATL) is a highly aggressive T cell malignancy, and has a poor prognosis. Recently, allogeneic-hematopoietic stem cell transplantation (allo-HSCT) has been suggested to improve the outcome. We retrospectively analyzed 15 patients with ATL who had received allo-HSCT in 2 institutions in Hokkaido, Japan. The median age of the patients was 57 years. The estimated 3-year overall survival (OS) and progression-free survival (PFS) rates were 73.3% and 66.7%, respectively. Calcineurin inhibitor dosage was reduced and administration was discontinued abruptly in 6 of the 15 patients for disease control; as a result, 4 (66.7%) of the 6 patients achieved complete response (CR) or partial response. Therefore, a graft-versus-leukemia/lymphoma (GVL) effect might be induced by discontinuation of immunosuppression. Thirteen of the 15 patients were followed up by monitoring HTLV-1 proviral DNA levels. In 10 of the 11 patients with positive HTLV-1 proviral DNA before allo-HSCT, HTLV-1 proviral DNA became undetectable at least once after allo-HSCT, and only 1 of the 5 patients in whom HTLV-1 proviral DNA became detectable after allo-HSCT relapsed. Compared to the results of past studies, these results show that allo-HSCT greatly improved the prognosis of ATL and suggest a contribution of the induction of a GVL effect.

Regulation of transforming growth factor-beta and bone morphogenetic protein signalling by transcriptional coactivator GCN5.

Smad proteins are intracellular signalling mediators of transforming growth factor‐β (TGF‐β) superfamily. In the nucleus, activated Smad complexes regulate transcriptional responses of the target genes in cooperation with transcriptional coactivators and corepressors. To identify new components of transcriptional complexes containing Smad proteins, we purified DNA‐binding proteins from human breast cancer MCF‐7 cell nuclear extract using a Smad‐binding DNA element as bait, and identified a coactivator GCN5 as a direct partner of activated Smad complexes. GCN5 is structurally similar to PCAF, which was previously identified as a coactivator for receptor‐regulated Smads (R‐Smads) for TGF‐β signalling pathways. GCN5 functions like PCAF, in that it binds to TGF‐β‐specific R‐Smads, and enhances transcriptional activity induced by TGF‐β. In addition, GCN5, but not PCAF, interacts with R‐Smads for bone morphogenetic protein (BMP) signalling pathways, and enhances BMP‐induced transcriptional activity, suggesting that GCN5 and PCAF have distinct physiological functions in vivo. Moreover, silencing of the GCN5 gene by RNA interference results in repression of transcriptional activities induced by TGF‐β. In conclusion we identified GCN5 as a Smad‐binding transcriptional coactivator which positively regulates both TGF‐β and BMP signalling pathways.

Excellent Outcome of Allogeneic Hematopoietic Stem Cell Transplantation Using a Conditioning Regimen with Medium-Dose VP-16, Cyclophosphamide and Total-Body Irradiation for Adult Patients with Acute Lymphoblastic Leukemia

We retrospectively evaluated the outcomes of 37 adult patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) conditioned with medium-dose VP-16 (VP, 30 mg/kg), cyclophosphamide (CY, 120 mg/kg), and fractionated total-body irradiation (TBI, 12 Gy) (medium-dose VP/CY/TBI). The median age of the patients was 26 years. Thirteen patients underwent transplantation from HLA-matched related donors (MRD), 18 patients underwent transplantation from HLA-matched unrelated donors (MUD), and 6 patients underwent transplantation from HLA-mismatched donors (MMD). Thirty-two patients received bone marrow and 4 patients received peripheral blood stem cells. Ten patients were Philadelphia chromosome-positive (Ph(+)) and 35 patients were in complete remission (CR) at transplantation. All of the patients achieved engraftment, and grade 3 organ toxicity before engraftment occurred in 27 patients. Grade II-III acute graft-versus-host disease (GVHD) and chronic GVHD (cGVHD) occurred in 15 and 18 patients, respectively. No patient developed grade IV acute GVHD (aGVHD) or died of GVHD. At median follow-up of 35.1 months, 32 patients were alive and all Ph(+) patients were alive. Three patients died of relapse and 2 died of transplant-related mortality (TRM). The actuarial 3-year overall survival (OS) rate, relapse rate, and TRM rate were 89.2%, 8.1%, and 5.4%, respectively. Non-CR at transplantation, MRD, and no aGVHD were significant adverse prognostic factors for survival. Medium-dose VP/CY/TBI for adult ALL patients was associated with lower relapse rate and no increase in toxicity, resulting in better survival.

HB Vaccination in the Prevention of Viral Reactivation in Allogeneic Hematopoietic Stem Cell Transplantation Recipients with Previous HBV Infection

Hepatitis B virus (HBV)-reverse seroconversion (RS) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a frequent late-onset complication in recipients with previous HBV infection. We followed 38 allo-HSCT recipients with previous HBV infection, and conducted posttransplant HB vaccine intervention in 13 recipients. First, we followed the recipients without any intervention (historic control) until 2003; hence, we commenced HB vaccination. Out of the patients who underwent transplantation after 2003, 13 recipients were immunized by a standard three-dose regimen after immunosuppressant cessation (vaccine group), whereas 12 recipients were observed without any intervention (nonvaccine group). Eight of the 13 historic control group recipients and 3 of the 12 nonvaccine group recipients, but none of the 13 vaccine group recipients, suffered HBV-RS. Cumulative risks of HBV-RS at 3 years post-HSCT in the historic control, nonvaccine and vaccine groups were 41%, 39%, and 0% respectively (P=.022). We therefore conclude that intervention with HB vaccines is significantly effective in preventing post-HSCT HBV-RS.

Successful micafungin (FK463) treatment of invasive pulmonary aspergillosis in a patient with acute lymphoblastic leukemia in a phase II study.

We treated a 52-year-old woman with acute lymphoblastic leukemia (ALL) who developed invasive pulmonary aspergillosis (IPA) as a result of neutropenia following remission-induction chemotherapy. Although serological test results, such as those for platelia and pastrex, were all negative and the serum level of β-D—glucan was low,Aspergillus DNA was detected in blood by the polymerase chain reaction method. A clinically documented diagnosis of IPA was made on the basis of chest x-rays, computed tomography scan findings, and the detection ofAspergillus DNA. Micafungin (FK463), a candin class anti-fungal agent, was administered at a dose of 75 to 150 mg/day, because other antifungal agents were not effective. The increase in serum concentration of micafungin was dose-dependent and was accompanied by improvement of symptoms and objective findings. Micafungin was effective for the treatment of IPA in this patient with ALL.

Relationship between Preexisting Anti-Varicella-Zoster Virus (VZV) Antibody and Clinical VZV Reactivation in Hematopoietic Stem Cell Transplantation Recipients

ABSTRACT Reactivation of latent varicella-zoster virus (VZV), presenting as localized zoster or as disseminated infection, is a common and potentially serious complication in hematopoietic stem cell transplantation (HSCT) recipients. We retrospectively studied anti-VZV immunoglobulin G titers by the immune adherence hemagglutination method after HSCT and also studied VZV DNA by real-time PCR during clinical VZV reactivation using cryopreserved serum samples. No significant difference was found between anti-VZV titers in 13 patients with VZV infection (localized zoster in 11 patients and disseminated zoster in 2 patients) and in 13 subjects without VZV infection at each time point after HSCT. Preexisting anti-VZV titers of disseminated zoster cases tended to be lower than those of localized zoster cases (P = 0.10). Serum VZV DNA copy numbers at the onset of disseminated zoster cases tended to be higher than those of localized zoster cases (P = 0.09). A strong inverse correlation was found between preexisting anti-VZV titer and serum VZV DNA at onset (r = −0.90, P = 0.006). In HSCT recipients, preexisting antibody does not prevent the development of VZV reactivation but may contribute to decreased viral load at onset, resulting in a mild clinical course.

Thrombotic microangiopathy after treatment with bortezomib and dexamethasone in a patient with multiple myeloma

Bortezomib (Bz) is extensively used for treating patients with multiple myeloma. There has been an accumulation of information on its efficacy and safety. Thrombotic disorders after treatment with Bz are rare, except for complication caused by tumor lysis syndrome. Here, we report a rare case of thrombotic microangiopathy (TMA) after treatment with Bz and dexamethasone (Dexa) in a patient with multiple myeloma. A 54-year-old Japanese man with refractory IgAjtypemultiple myeloma was treated with Bz (1.3 mg/m, days 1, 4, 8, and 11 in 21-day cycles) and Dexa (20 mg/body, days 1, 2, 4, 5, 8, 9, 11, and 12) in November 2007. He had received high-dose melphalan with autologous peripheral blood stem cell transplantation in May 2005 and allogeneic bone marrow transplantation after a reduced-intensity conditioning regimen [fludarabine, busulfan, and 4 Gy of total body irradiation (TBI)] in November 2006. He had dry skin and bronchiolitis obliterans organizing pneumonia (BOOP) caused by chronic graft-versus-host disease (GVHD), and he was treated with oral tacrorimus (1.2 mg/ day) and prednisolone (10 mg/day) and showed improvement. He had not had TMA, thrombotic thrombocytoprnic purpura (TTP), hemolytic uremic syndrome (HUS) or veno-occlusive-disease (VOD). The patient complained of chest pain and dyspnea on the fifth day in the first course of treatment with Bz and Dexa. His oxygen saturation (SpO2) was 88% in room air. Computed tomography of the chest showed ground glass opacities throughout the bilateral upper and middle lobes (Fig. 1). He suffered from severe interstitial pneumonia (IP). Since we thought that Bz was the cause of his pneumonia, we administered methylpredonisolone at 1,000 mg/ body intravenously for 3 days and stopped the treatment with Bz and Dexa. His pneumonia improved rapidly and did not recur despite steroid tapering off. Three days after the onset of IP (first course, day 8), he had scattered petechiae and suggillation. His consciousness was clear and vital signs were normal. Results of laboratory tests are shown in Tables 1 and 2. Anemia and thrombocytopenia had progressed, and aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and indirect bilirubin were elevated and haptoglobin was decreased. Coombs test results were negative. Erythrocyte fragmentation ratio was 12.7% (Fig. 2). These data suggested microangiopathic hemolytic anemia. Decreased fibrinogen and extended prothrombin time observed by coagulation tests appeared 2 days before this event. Activity of ADAMTS-13 was slightly low (Table 2) and an inhibitor of ADAMTS-13 was not detected. Cytomegalovirus antigens were not detected, and beta-D-glucan, candida antigens and aspergillus antigens were normal. Bacterial cultures in sputa, stools, and urine were negative. We thought he suffered from TMA and administered fresh frozen plasma (240 ml/day) and haptoglobin (2,000 U/day). His symptoms improved gradually. Within 20 days, his laboratory data returned to the levels before treatment with Bz and Dexa. TMA is thought to be caused by endothelial damage derived from high-dose chemotherapy, TBI, GVHD, immunosuppressive agents and opportunistic infections in R. Morita (&) S. Hashino S. Shirai N. Fujita M. Onozawa K. Kahata T. Kondo M. Asaka Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan e-mail: r-mori@f3.dion.ne.jp

Efficacy of etoposide, cyclophosphamide, and total body irradiation in allogeneic bone marrow transplantation for adult patients with hematological malignancies

Abstract:  Introduction:  A combination of fractionated total body irradiation (TBI) with etoposide (VP‐16) and cyclophosphamide (CY) as a preconditioning regimen (VP/CY/TBI) has been reported to be safe and effective for both adults and children undergoing allogeneic bone marrow transplantation (allo‐BMT). However, the reported doses of VP‐16 were different. We evaluated the efficacy and safety of a VP‐16 (at less than the usual dose)/CY/TBI regimen for adults with hematological malignancies who are required to receive allo‐BMT.

Increased Proportion of HLA-Class-I-Specific Natural Killer Cell Receptors (CD94) on Peripheral Blood Mononuclear Cells after Allogeneic Bone Marrow Transplantation

In the present study, we investigated the inhibitory natural killer cell receptor (NKR) expression of CD94/NKG2A on PBMC after allogeneic bone marrow transplantation (BMT). The proportion of CD94 expression on PBMC was higher in patients without chronic graft-versus-host disease (cGVHD) and also in cGVHD patients with good response to conventional immunosuppressive therapy than in cGVHD patients with poor response. Also, the proportions of CD94+/CD3+ cells and CD94+/CD8+ cells were higher in cGVHD patients showing good response. In addition, the proportion of NKG2A-expressing cells was higher in patients without cGVHD than in patients with cGVHD. Therefore, chronic allostimulation after allo-BMT may augment the proportion of CD94/NKG2A-positive cells, and these cells may play some role in the regulation of alloresponse in some patients.