Hironari Niiya

Pre-emptive therapy against cytomegalovirus (CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan.

From April 1998 to March 2000, a cytomegalovirus (CMV) antigenemia-guided pre-emptive approach for CMV disease was evaluated in 77 adult patients who received allogeneic hematopoietic stem cell transplantation at the National Cancer Center Hospital. A CMV antigenemia assay was performed at least once a week after engraftment. High-level antigenemia was defined as a positive result with 10 or more positive cells per 50 000 cells and low-level antigenemia was defined as less than 10 positive cells. Among the 74 patients with initial engraftment, 51 developed positive antigenemia. Transplantation from alternative donors and the development of grade II–IV GVHD were independent risk factors for positive antigenemia. Ganciclovir was administered as pre-emptive therapy in 39 patients in a risk-adapted manner. None of the nine low-risk patients with low-level antigenemia as their initial positive result developed high-level antigenemia even though ganciclovir was withheld. Only one patient developed early CMV disease (hepatitis) during the study period. CMV antigenemia resolved in all but two cases, in whom ganciclovir was replaced with foscarnet. In eight patients, however, the neutrophil count decreased to 0.5 × 109/l or less after starting ganciclovir, including three with documented infections and two with subsequent secondary graft failure. The total amount of ganciclovir and possibly the duration of high-dose ganciclovir might affect the incidence of neutropenia. We concluded that antigenemia-guided pre-emptive therapy with a decreased dose of ganciclovir and response-oriented dose adjustment might be appropriate to decrease the toxicity of ganciclovir without increasing the risk of CMV disease. Bone Marrow Transplantation (2001) 27, 437–444.

Response-oriented preemptive therapy against cytomegalovirus disease with low-dose ganciclovir : a prospective evaluation

BACKGROUND Preemptive therapy against cytomegalovirus (CMV) disease has succeeded in reducing the incidence of CMV disease, but the toxicity of ganciclovir remains problematic. METHODS We prospectively evaluated the efficacy and toxicity of a preemptive protocol with ganciclovir at a reduced initial dose in 40 patients who achieved engraftment after allogeneic hematopoietic stem cell transplantation. RESULTS Twenty-three (58%) patients had high-risk features, including transplant from an HLA-mismatched or unrelated donor, or associated acute graft-versus-host disease. CMV antigenemia assay was performed weekly, and ganciclovir was started in a risk-adapted manner, in which the initial dose of ganciclovir was fixed at 5 mg/kg/d and then adjusted based on the results of a weekly CMV antigenemia assay. In this protocol, 23 (58%) patients demonstrated positive antigenemia, and 19 (48%) received a preemptive administration of ganciclovir. Only one patient had CMV disease in the gastrointestinal system, which was successfully treated with a regular therapeutic dose of ganciclovir. Consequently, the total dose of ganciclovir was significantly less than that in a previous protocol using the conventional double dose (5 mg/kg twice daily) of ganciclovir (134 mg/kg vs. 190 mg/kg on average, P=0.046). There were no significant toxicities attributed to ganciclovir, except for neutropenia <0.5 x 109/L, which developed in three patients for 3, 4, and 14 days, respectively, with granulocyte colony-stimulating factor support. CONCLUSION Preemptive therapy with a low initial dose of ganciclovir appeared to be effective even in high-risk patients. Further randomized controlled trial is warranted.

Successful application of nonmyeloablative transplantation for paroxysmal nocturnal hemoglobinuria.

OBJECTIVE Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder that manifests as hemolytic anemia, venous thrombosis, and deficient hematopoiesis. Although allogeneic hematopoietic stem cell transplantation is considered the only curative therapeutic measure, transplant-related mortality is not negligible. Several studies supported the use of nonmyeloablative stem cell transplantation (NST) for patients of advanced age or with organ dysfunction. Hence, we used NST in a PNH patient who suffered from acute renal failure due to repeated episodes of hemolysis. MATERIALS AND METHODS We performed NST using a conditioning regimen consisting of cladribine 0.11 mg/kg x 6, busulfan 4 mg/kg x 2, and rabbit anti-thymocyte globulin 2.5 mg/kg x 2. He received peripheral blood stem cells from his human leukocyte antigen-matched brother. Prophylaxis against graft-vs-host disease was performed with cyclosporine A alone. Chimerism of peripheral blood mononuclear cells was evaluated serially using short tandem repeat analysis and flow cytometry. RESULTS No meaningful regimen-related toxicities were documented. Donor chimerism of 90 to 100% was achieved on day 14 and thereafter. The patient is doing well, without any recurrence of hemolysis 6 months after transplant. Follow-up chimerism studies confirmed stable and functioning donor-type hematopoiesis. CONCLUSIONS NST may become a safe and curative approach in patients with PNH. Further studies are needed to establish the role of NST for treatment of PNH.

Suspected delayed immune recovery against cytomegalovirus after reduced-intensity stem cell transplantation using anti-thymocyte globulin.

A reduced-intensity hematopoietic stem cell transplantation (RIST) regimen was developed to induce immunosuppression to facilitate the engraftment of donor cells. However, there have been concerns that the incidence of opportunistic infection may increase after this procedure. To address this problem, we retrospectively analyzed the medical records of 24 RIST recipients who were treated over a recent 16-month period for comparison with 31 recipients of conventional allogeneic transplantation (CST). The RIST regimen consisted of cladribine (0.66 mg/kg), busulfan (8 mg/kg), and rabbit anti-thymocyte globulin (ATG; 5–10 mg/kg). All of the patients received allogeneic peripheral blood stem cells from an HLA-identical or one-locus mismatched related donor. Although the incidence of positive CMV antigenemia was comparable between the two groups (58% vs 68%), RIST patients developed positive antigenemia significantly sooner than did CST patients (P = 0.01) and showed higher initial and maximum antigenemia values (P = 0.026 and P = 0.003, respectively). These findings may suggest that immune recovery against CMV was delayed after our RIST procedure, but this did not directly translate into an increase in clinically significant CMV disease. Early therapeutic intervention with ganciclovir might play a role in preventing the progression of early CMV infection to CMV disease.Bone Marrow Transplantation (2002) 29, 237–241. doi:10.1038/sj.bmt.1703351

Impact of stem cell source and conditioning regimen on erythrocyte recovery kinetics after allogeneic haematopoietic stem cell transplantation from an ABO-incompatible donor

Summary. We evaluated erythrocyte recovery in 121 allogeneic haematopoietic stem cell transplantation (HSCT) recipients. There were 35 major and minor ABO‐incompatible transplants, respectively, including 10 bi‐directionally ABO‐incompatible transplants. The use of peripheral blood stem cells facilitated erythrocyte recovery, regardless of the presence or absence of major ABO‐incompatibility, and was associated with a frequent detection of anti‐host isohaemagglutin early after minor ABO‐incompatible transplantation, which was not associated with clinically relevant haemolysis. The use of a reduced‐intensity regimen combining a purine analogue and busulphan did not delay erythrocyte recovery after major ABO‐incompatible transplantation, suggesting this regimen had a strong activity against host plasma cell.

Limited efficacy of lamivudine against hepatitis B virus infection in allogeneic hematopoietic stem cell transplant recipients

BACKGROUND Reactivation of chronic hepatitis B virus (HBV) infection is a major complication when HBV carriers receive immunosuppressive therapy. Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) carry the highest risk of fatal HBV disease (up to 12%). METHODS In an attempt to identify a suitable procedure for the prevention and management of HBV reactivation, the administration of lamivudine over the course was tested in two patients. RESULTS Generally, the patients transplant courses were successfully managed despite their difficult clinical situations: a high HBV load before transplant in one patient and intense steroid therapy for complicated acute graft-versus-host disease (GVHD) in the other patient. However, one patient showed a reactivation of HBV after discontinuing lamivudine and the other showed persistently high DNA polymerase activity despite prolonged administration of lamivudine. CONCLUSIONS We concluded that lamivudine could have a place in the management of patients who suffer from chronic HBV infection and who are undergoing allogeneic HSCT. However, the efficacy of lamivudine seemed to be limited compared with other settings, including solid organ transplantation and autologous HSCT.