Shinichi Kako

Long‐term ultra‐low‐dose acyclovir against varicella‐zoster virus reactivation after allogeneic hematopoietic stem cell transplantation

To evaluate the efficacy of long‐term prophylaxis with ultra‐low‐dose acyclovir against varicella‐zoster virus (VZV) reactivation, we analyzed the records of 242 Japanese adult patients who underwent allogeneic hematopoietic stem cell transplantation for the first time from 1995 to 2006 at our hospital. We started long‐term oral acyclovir at 200 mg/day in July 2001. Acyclovir was continued until the end of immunosuppressive therapy and at least 1 year after transplantation. Sixty‐six patients developed VZV reactivation at a median of 248 days after HSCT, with a cumulative incidence of 34.7%. Only one breakthrough reactivation occurred during long‐term acyclovir, which responded well to therapeutic dose of valacyclovir. The use of long‐term acyclovir was the only independent determinant that significantly decreased the overall incidence of VZV reactivation (20% vs. 50%, P < 0.0001). With this prophylaxis, visceral dissemination and serious complications other than post‐herpetic neuralgia was completely eliminated, and thereby need for hospitalization was significantly reduced (21% vs. 71%, P = 0.0034). Fifteen of the 57 patients who discontinued acyclovir developed VZV reactivation, with a cumulative incidence of 32.1%. VZV reactivation following discontinuation tended to occur in patients who were receiving immunosuppressive therapy at the cessation of acyclovir. These findings suggested that long‐term prophylaxis of ultra‐low‐dose acyclovir resulted in a successful prevention of severe VZV‐related symptoms and death, with a significantly decreased overall incidence of VZV reactivation. Prolongation of prophylactic acyclovir on profound immunosuppression might be important for thorough suppression of VZV reactivation. Am. J. Hematol., 2008.

EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization

The ecotropic viral integration site-1 (EVI-1) is a nuclear transcription factor and has an essential function in the proliferation/maintenance of haematopoietic stem cells. Aberrant expression of EVI-1 has been frequently found in myeloid leukaemia as well as in several solid tumours, and is associated with a poor patient survival. It was recently shown that EVI-1 associates with two different histone methyltransferases (HMTs), SUV39H1 and G9a. However, the functional roles of these HMTs in EVI-1-mediated leukemogenesis remain unclear. In this study, we showed that EVI-1 physically interacts with SUV39H1 and G9a, but not with Set9. Immunofluorescence analysis revealed that EVI-1 colocalizes with these HMTs in nuclei. We also found that the catalytically inactive form of SUV39H1 abrogates the transcriptional repression mediated by EVI-1, suggesting that SUV39H1 is actively involved in EVI-1-mediated transcriptional repression. Furthermore, RNAi-based knockdown of SUV39H1 or G9a in Evi-1-expressing progenitors significantly reduced their colony-forming activity. In contrast, knockdown of these HMTs did not impair bone marrow immortalization by E2A/HLF. These results indicate that EVI-1 forms higher-order complexes with HMTs, and this association has a role in the transcription repression and bone marrow immortalization. Targeting these HMTs may be of therapeutic benefit in the treatment for EVI-1-related haematological malignancies.

Clinical features of late cytomegalovirus infection after hematopoietic stem cell transplantation

Late cytomegalovirus (CMV) disease beyond day 100 after hematopoietic stem cell transplantation (HSCT) has become an increasing problem after the introduction of preemptive ganciclovir (GCV) administration. To clarify the risk factors and outcome for late CMV reactivation and disease, we retrospectively analyzed the records of 101 Japanese adult patients who underwent allogeneic HSCT between 1998 and 2005 at our hospital. Fifty-one developed late positive CMV antigenemia, with a cumulative incidence of 53%. Recipient CMV seropositivity, the use of alemtuzumab, chronic GVHD, and high-dose steroids were significantly associated with late positive antigenemia. Eight patients developed late CMV disease, with a cumulative incidence of 8%, including retinitis and gastrointestinal disease. None progressed to a fatal disease. The use of alemtuzumab was identified as an independent significant risk factor for late CMV disease, although it was not associated with increased non-relapse mortality. Among the 51 patients with late positive antigenemia, 28 had consistently less than three positive cells, 25 of whom showed negative conversion without antiviral agents. In conclusion, late CMV antigenemia appeared to develop frequently, especially in patients with profound immune suppression; however, a fatal outcome could be prevented by optimal preemptive therapy. Low-level antigenemia may not require antiviral treatments.

Case report: persistent cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation using in vivo alemtuzumab: emergence of resistant CMV due to mutations in the UL97 and UL54 genes.

Addition of in vivo alemtuzumab to the conditioning regimen enabled 2‐ or 3‐locus‐mismatched hematopoietic stem cell transplantation with an acceptable incidence of graft‐versus‐host‐disease. However, the procedure was associated with a high incidence of cytomegalovirus (CMV) reactivation. Although preemptive therapy with ganciclovir prevented successfully severe CMV diseases and CMV‐related mortality, a patient developed persistent positive CMV antigenemia for more than 1 year after transplantation and CMV disease, despite the use of ganciclovir and foscarnet. The in vitro susceptibility assay showed that the clinical isolate was resistant to foscarnet, moderately resistant to ganciclovir, but sensitive to cidofovir. Therefore, cidofovir was administered. CMV antigenemia became negative within 2 weeks and never developed again. Nucleotide sequence of the UL54 and UL97 of the clinical isolate showed 4 amino acid substitutions (V11L, Q578H, S655L, and G874R) in UL54 and 2 mutations (A140V and A594V) in UL97 compared with the Towne and AD169 strains. Ganciclovir resistance was suspected to be caused by both A594V of UL97 and Q578H of UL54, whereas foscarnet resistance was due mainly to Q578H of UL54. In conclusion, the in vitro susceptibility assay as well as nucleotide sequence of clinical isolate is important to choose appropriate antiviral agents for patients who have persistent CMV reactivation after stem cell transplantation. J. Med. Virol. 80:1769–1775, 2008.

Conventional allogeneic hematopoietic stem cell transplantation for lymphoma may overcome the poor prognosis associated with a positive FDG‐PET scan before transplantation

A positive scan in pretransplantation fluorine‐18 fluorodeoxyglucose positron emission tomography (FDG‐PET) has been shown to be associated with a poor prognosis in patients with lymphoma undergoing high‐dose chemotherapy followed by autologous stem cell transplantation (ASCT). For those with a positive FDG‐PET scan, treatment that includes allogeneic stem cell transplantation (allo‐SCT) may be an alternative. However, it is uncertain whether allo‐SCT can overcome a poor prognosis. Therefore, we conducted a retrospective analysis of 14 patients with lymphoma who had undergone FDG‐PET scan within one month before allo‐SCT at our institution. Eleven patients were FDG‐PET‐positive and three were negative. With a median follow‐up of 17 months (range: 6–44) after allo‐SCT, the cumulative incidence of progression was 29.3% in FDG‐PET‐positive patients and 0% in the FDG‐PET‐negative patients. Four of the 11 patients who had post‐transplantation FDG‐PET showed FDG‐avid lesions on the first post‐transplantation scan. In two of the four, regression of the lesions was observed during the scheduled reduction of immunosuppressant without donor lymphocyte infusion and remained without progression at the last follow‐up (34 and 8 months). Durable responses after allo‐SCT, at least with conventional conditioning regimens, can be expected in patients with FDG‐PET‐positive lesions before transplantation. Thus, conventional allo‐SCT could be an attractive modality compared to ASCT for patients with positive FDG‐PET after the completion of conventional salvage chemotherapy, and particularly for patients with T and NK‐cell lymphomas. Am. J. Hematol., 2008.

Pharmacokinetics of micafungin in patients undergoing allogeneic hematopoietic stem cell transplantation.

Micafungin (MCFG) is an antifungal agent that is widely used for the treatment of invasive fungal infection. Although the pharmacokinetics of MCFG is considered to depend on the hepatic metabolism, the impact of hepatic function on the pharmacokinetics of MCFG has been inconsistent among previous studies. The object of this study was to evaluate the relationship between plasma MCFG concentration and clinical and laboratory data.