Mutsumi Takahata

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.

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.

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.

Hepatitis B virus (HBV) reverse seroconversion (RS) can be prevented even in non‐responders to hepatitis B vaccine after allogeneic stem cell transplantation: long‐term analysis of intervention in RS with vaccine for patients with previous HBV infection

Reactivation of hepatitis B virus (HBV) infection, reverse seroconversion (RS), is a serious complication after allogeneic stem cell transplantation (alloHSCT). We previously conducted a post‐transplant hepatitis B vaccine intervention trial and demonstrated the vaccine efficacy in preventing HBV‐RS. This report is an update of the hepatitis B vaccine study.

Reduced intensity conditioning regimen with fludarabine, busulfan, and low-dose TBI (Flu-BU2-TBI): clinical efficacy in high-risk patients.

Reduced intensity conditioning (RIC) regimens are widely used in allogeneic stem cell transplantation (SCT). In this study, we retrospectively investigated the clinical outcomes of RIC with fludarabine (Flu; 180 mg/m2), intravenous busulfan (BU; 6.4 mg/kg) or oral BU (8 mg/kg), and low‐dose total body irradiation (TBI; 4 Gy) (Flu‐BU2‐TBI) in 66 patients (median age: 54.5 years) with various hematological malignancies. Thirty‐eight patients (58%) were high‐risk patients (median age: 56 years). The overall survival rate at 2 years of the high‐risk patients was 64.5%, which was comparable to the survival rate of 70.9% in standard‐risk patients (P = 0.68). The relapse rates at 2 years in the standard‐risk and high‐risk patients were 16 and 28%, respectively, and day 100 treatment‐related mortality rates were 0 and 6%, respectively. The Flu‐BU2‐TBI regimen for high‐risk patients showed therapeutic effects equivalent to those for standard‐risk patients and favorable outcomes compared with those of other previous RIC regimens. Am. J. Hematol., 2010.

Durable Remission of Sézary Syndrome after Unrelated Bone Marrow Transplantation by Reduced-Intensity Conditioning

A 22-year-old Japanese man was diagnosed with Sézary syndrome with large cell transformation. His skin lesions persisted after treatment with 7 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), psoralen and ultraviolet light A, and total skin electron beam irradiation. He subsequently underwent allogeneic bone marrow transplantation by reduced-intensity conditioning from a human leukocyte antigen-identical unrelated donor. He developed grade II of acute graft-versus-host disease and extensive-type chronic graft-versus-host disease. He has no signs of disease 36 months after the transplantation. The prognosis of patients with advanced stage of mycosis fungoides or Sézary syndrome is very poor. Allogeneic hematopoietic stem cell transplantation, especially by reduced-intensity conditioning, is expected to become a curative treatment option, and graft-versus-tumor effect might play a critical role for sustained remission.

Increased risk of bacterial infection after engraftment in patients treated with allogeneic bone marrow transplantation following reduced-intensity conditioning regimen

A. Shigematsu, S. Yamamoto, J. Sugita, T. Kondo, M. Onozawa, K. Kahata, T. Endo, S. Shiratori, S. Ota, K. Yamaguchi, K. Wakasa, M. Takahata, H. Goto, S. Ito, R. Takemura, J. Tanaka, S. Hashino, M. Nishio, T. Koike, M. Asaka, M. Imamura. Increased risk of bacterial infection after engraftment in patients treated with allogeneic bone marrow transplantation following reduced‐intensity conditioning regimen.
Transpl Infect Dis 2010: 12: 412–420. All rights reserved

Successful Reduced-Intensity Stem Cell Transplantation With Cord Blood for a Poor-Prognosis Adult with Refractory Chronic Active Epstein-Barr Virus Infection

A 56-year-old woman with a poor-prognosis chronic active Epstein-Barr virus (CAEBV) infection underwent reduced-intensity stem cell transplantation (RIST) using cryopreserved cord blood (CB). Administration of EBV-seronegative CB cells following a reduced-intensity conditioning regimen was effective and well tolerated. Complete remission with no symptoms, low titers of EBV-related antibodies, and an undetectable level of EBV DNA in peripheral blood mononuclear cells continued for 16 months after RIST This report is the first of successful RIST with CB for an adult with CAEBV infection. The results also show that a graft-versus-CAEBV effect can be achieved in an allogeneic hematopoietic stem cell transplantation setting.

Successful treatment with allogeneic peripheral blood stem cell transplantation and granulocyte transfusion for severe aplastic anemia with sinusitis.

Abstract: A 43‐year‐old woman with severe aplastic anemia (SAA) received anti‐thymocyte globulin and cyclosporin A (CyA) and achieved hematological remission. Although she had maintained hematological remission, the disease relapsed 10 months after arbitrary discontinuance of maintenance therapy with CyA. Resumption of CyA therapy was not effective, and her condition became complicated with progressive sinusitis with bone destruction, which was refractory to antibiotics, antifungal agents, granulocyte colony‐stimulating factor, and surgical drainage. Because of the necessity for early neutrophil recovery (to resolve the infection), we proceeded with a combination therapy using allogeneic peripheral blood stem cell transplantation (PBSCT) promptly followed by granulocyte transfusion (GTX) from the same human leukocyte antigen‐identical donor rather than carrying out a second immunosuppressive therapy. The patient showed temporal resolution of infection on the second day after a single GTX. Although the patient had pneumonia on day 11, it was resolved promptly after engraftment on day 16. This report suggests the clinical utility of a salvage therapy with allogeneic PBSCT followed by GTX in a particular case of recurrent SAA with refractory infections.