Hideho Henzan

Cidofovir for treating adenoviral hemorrhagic cystitis in hematopoietic stem cell transplant recipients

Summary:Adenovirus (AdV) infection is an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. We treated 16 patients with AdV hemorrhagic cystitis (HC) following HSCT with cidofovir (CDV; 1 mg/kg/day, three times weekly for 3 weeks). Patients included 10 males and six females with a median age of 50 years (range 10–62). Two of the 16 patients were unevaluable because of early death from nonadenoviral causes. CDV therapy cleared AdV from urine in 12 of 14 patients (86%). Of 14 patients, 10 (71%) showed clinical improvements in HC. Among 14 patients, seven (50%) had avoided renal damage, the most important CDV toxicity. One patient previously treated with foscarnet for cytomegalovirus (CMV) required hemodialysis, and CDV treatment was discontinued. In another patient, CDV treatment was discontinued because of grade 2 nephrotoxicity. Four patients became positive for CMV antigenemia while being treated with CDV, and two developed herpes simplex virus (HSV) stomatitis while being treated with CDV. CDV proved effective in treating AdV HC in transplant patients. However, CDV at 1 mg/kg/day given three times weekly failed to prevent breakthrough infection with CMV and HSV in some patients.

A phase I-II trial of autologous peripheral blood stem cell transplantation in the treatment of refractory autoimmune disease

Objectives: To carry out a phase I-II trial to elucidate the feasibility and efficacy of high dose cyclophosphamide (CY) supported by autologous peripheral blood stem cell transplantation (PBSCT) in the treatment of severe and refractory autoimmune disease (AD). Methods: Peripheral blood stem cells (PBSCs) were mobilised during haematological recovery after relatively high dose CY (2 g/m2) for 2 days, followed by administration of granulocyte colony stimulating factor. After collecting PBSCs—more than 2×106 CD34+ cells/kg—by apheresis, CD34+ cells were immunologically selected and cryopreserved. Eight patients were enrolled—five had systemic sclerosis (SSc) alone, one had SSc with systemic lupus erythematosus, one amyopathic dermatomyositis (ADM), and one Wegener’s granulomatosis (WG). All of the patients were treated with high dose CY (50 mg/kg) for 4 days and autologous PBSCT. Results: Haematopoietic reconstitution was rapid and sustained. Toxicity due to the regimen included various infections such as pneumonia, sepsis, cystitis, herpes zoster, and acute heart failure. However, there was no treatment related mortality. Encouraging results were obtained after autologous PBSCT. Sclerosis of the skin was markedly improved in all of the patients with SSc. Interstitial pneumonia (IP), evaluated by Pao2, serum KL-6 levels, and pulmonary high resolution computed tomography, improved significantly. In a patient with ADM, severe and progressive IP also improved markedly. In a patient with WG, the size of the left orbital granuloma decreased substantially, resulting in reduction of the exophthalmos. Conclusions: These observations suggest that high dose CY with autologous PBSCT is feasible and may be effective in the treatment of severe and refractory AD.

Detection of human herpesvirus-8 in peripheral blood mononuclear cells from adult Japanese patients with multicentric Castleman's disease.

Summary. Human herpesvirus‐8 (HHV‐8) encodes viral homologues of cellular genes, including viral interleukin 6 (vIL‐6), which induces endogenous human IL‐6 (hIL‐6) secretion. Unregulated overproduction of hIL‐6 in lymph nodes (LN) is thought to be responsible for the systemic manifestations of multicentric Castlemans disease (MCD). In the present study, we assessed the presence of HHV‐8 and HHV‐8‐encoded viral homologues in LN and peripheral blood mononuclear cells (PBMC) from adult Japanese patients with MCD. HHV‐8 DNA was amplified by nested polymerase chain reaction (PCR) and was detected in LN from 13 out of 16 MCD patients (81%). HHV‐8 DNA was also detected in PBMC from six out of seven patients (86%) whose LN were positive for HHV‐8 DNA. Because mRNA could not be successfully extracted from LN sections that were either formalin‐fixed or embedded in paraffin, we examined the expression of mRNA for HHV‐8‐encoded viral homologues, such as vIL‐6, vBCL‐2, vCyclin‐D and viral G‐protein‐coupled receptor (vGPCR) by nested reverse transcription (RT)‐PCR in PBMC from 10 MCD patients. However, mRNA of these HHV‐8‐encoded viral homologues was not detected in any patients tested. Although our results do not indicate a role for HHV‐8‐encoded viral homologues in the pathogenesis of MCD, they do suggest that HHV‐8 infection may be associated with MCD in adult Japanese patients.

Pretransplantation anti-CCR4 antibody mogamulizumab against adult T-cell leukemia/lymphoma is associated with significantly increased risks of severe and corticosteroid-refractory graft-versus-host disease, nonrelapse mortality, and overall mortality

PURPOSE Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is one important treatment option for patients with aggressive adult T-cell leukemia/lymphoma (ATLL). Mogamulizumab (anti-CCR4 monoclonal antibody; Mog) was recently approved as a treatment for ATLL in Japan. Major concerns exist about the possible adverse effects of pretransplantation Mog because Mog depletes regulatory T cells for several months. We assessed the impact of pretransplantation Mog on clinical outcomes after allo-HSCT. PATIENTS AND METHODS We included 996 allo-HSCT recipients age 70 years or younger with aggressive ATLL who were given the diagnosis between 2000 and 2013 and who received intensive chemotherapy by multiple chemotherapeutic drugs as first-line therapy. Before allo-HSCT, 82 patients received Mog with a median interval of 45 days from the last Mog to allo-HSCT. RESULTS Pretransplantation Mog was associated with an increased risk of grade 3 to 4 acute graft-versus-host disease (GVHD; relative risk, 1.80; P < .01) and refractoriness to systemic corticosteroid for acute GVHD (relative risk, 2.09; P < .01). One-year cumulative incidence of nonrelapse mortality was significantly higher in patients with pretransplantation Mog compared with those without (43.7% v 25.1%; P < .01). The probability of 1-year overall survival was also significantly inferior in patients with pretransplantation Mog compared with those without (32.3% v 49.4%; P < .01). In particular, use of Mog with intervals < 50 days to allo-HSCT was associated with a dismal clinical outcome. CONCLUSION Pretransplantation Mog was significantly associated with an increased risk of GVHD-related mortality, which supports the relevance of CCR4-expressing Tregs after allo-HSCT in humans. In clinical practice, Mog should be cautiously used for patients with ATLL who are eligible for allo-HSCT.

Rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease

We prospectively evaluated the safety and efficacy of the anti-CD20 chimeric monoclonal antibody rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Seven patients were treated with 375 mg/m2 rituximab weekly for 4 consecutive weeks. Rituximab was well tolerated with no severe toxicity observed during treatment. At 1 year, 3 patients showed a partial response to rituximab therapy, 3 had stable disease, and 1 had progressive disease. Rituximab allowed a reduction in the dose of steroids in 4 patients. Responsive manifestations included mild to moderate skin and oral lesions, and immune hemolytic anemia, and thrombocytopenia. Severe manifestations involving the skin, fascia, and eye did not respond to treatment. These observations suggest that rituximab therapy may be effective for select patients with corticosteroid-refractory chronic GVHD that is not advanced.

Long-term outcomes of autologous PBSCT for peripheral T-cell lymphoma: retrospective analysis of the experience of the Fukuoka BMT group

Peripheral T-cell lymphoma (PTCL) is generally characterized by poor prognosis after conventional chemotherapy compared with aggressive B-cell lymphoma. To elucidate the role of high-dose chemotherapy (HDCT) with auto-SCT, we retrospectively analyzed the outcomes of 39 patients with PTCL who received HDCT and auto-SCT between 1990 and 2005. Eleven patients were histologically typed as angioimmunoblastic, nine as anaplastic large-cell lymphoma, seven as natural killer/T-cell lymphoma and twelve as PTCL unspecified. Clinical conditions at transplantation were complete response (CR) in 27 patients and non-CR in 12 patients. Thirty-two patients received a pre-transplant conditioning regimen (MCEC) comprising ranimustine, carboplatin, etoposide and CY, and seven did other TBI-based regimens. Rapid engraftment was obtained in all cases, and transplant-related death was not seen. An estimated 5-year OS was 62.1% with a median follow-up of 78 months. The 5-year OS was significantly higher in patients transplanted during complete response than in those during other disease status (71.4% vs 27.3%, P=0.046). HDCT supported by auto-SCT may therefore be effective as consolidation in CR for PTCL treatment.

Influence of transplanted dose of CD56+ cells on development of graft-versus-host disease in patients receiving G-CSF-mobilized peripheral blood progenitor cells from HLA-identical sibling donors.

Summary:We investigated effects of variations in the cellular composition of G-CSF-mobilized peripheral blood progenitor cell (G-PBPC) allografts on clinical outcomes of allogeneic PBPC transplantation. We retrospectively analyzed transplanted doses of various immunocompetent cells from 27 HLA-identical sibling donors in relation to engraftment, incidence of graft-versus-host disease (GVHD), and survival. Significant variability was documented in both absolute numbers and relative proportions of CD34+, CD2+, CD3+, CD4high+, CD4+25+, CD8high+, CD19+, CD56+, and CD56+16+ cells contained in these allografts. Stepwise Cox regression analysis revealed that the CD56+ cell dose was significantly inversely correlated with the incidence of GVHD. Thus, there was a significantly higher incidence of grade II acute GVHD in patients receiving a lower CD56+16+ cell dose (hazard ratio (HR) 0.0090; 95% confidence interval (CI), <0.00001–3.38; P=0.031), a higher incidence of chronic GVHD in those receiving allografts with a lower CD56+16+ to CD34+ ratio (HR <0.00001; 95% CI <0.00001–0.0007; P=0.0035), and a higher incidence of extensive chronic GVHD in those receiving allografts with a lower CD56+ to CD34+ ratio (HR <0.00001; 95% CI <0.00001–0.053; P=0.0083). These results suggest that CD56+ cells in G-PBPC allografts from HLA-identical sibling donors may play an important role in preventing the development of GVHD.

Mobilization of Human Lymphoid Progenitors after Treatment with Granulocyte Colony-Stimulating Factor

Hemopoietic stem and progenitor cells ordinarily residing within bone marrow are released into the circulation following G-CSF administration. Such mobilization has a great clinical impact on hemopoietic stem cell transplantation. Underlying mechanisms are incompletely understood, but may involve G-CSF-induced modulation of chemokines, adhesion molecules, and proteolytic enzymes. We studied G-CSF-induced mobilization of CD34+CD10+CD19−Lin− and CD34+CD10+CD19+Lin− cells (early B and pro-B cells, respectively). These mobilized lymphoid populations could differentiate only into B/NK cells or B cells equivalent to their marrow counterparts. Mobilized lymphoid progenitors expressed lymphoid- but not myeloid-related genes including the G-CSF receptor gene, and displayed the same pattern of Ig rearrangement status as their bone marrow counterparts. Decreased expression of VLA-4 and CXCR-4 on mobilized lymphoid progenitors as well as multipotent and myeloid progenitors indicated lineage-independent involvement of these molecules in G-CSF-induced mobilization. The results suggest that by acting through multiple trans-acting signals, G-CSF can mobilize not only myeloid-committed populations but a variety of resident marrow cell populations including lymphoid progenitors.

Infectious complications in patients receiving autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases

Abstract: Long‐term analysis of infectious complication after high‐dose immunosuppressive therapy with CD34‐selected autologous hematopoietic stem cell transplantation for patients with severe autoimmune diseases (AD) was performed. Theoretically, CD34 selection can reduce the risk of reinfusion of autoreactive lymphocytes. However, it is also associated with a significant reduction in T cells, natural killer cells, and monocytes, which in turn may compromise immune reconstitution, thereby increasing the risk of infection. Moreover, AD compromises host immunity and causes organ damage resulting in dysfunction of the cutaneous or mucosal barrier. In this study, the incidence rate of infections is reported in 14 patients who underwent high‐dose (200 mg/kg) cyclophosphamide therapy followed by reinfusion of CD34‐selected autologous peripheral blood stem cells. Bacterial complication occurred in 3 of 14 (21%) patients. Cytomegalovirus reactivation and adenovirus hemorrhagic cystitis were observed in 9 (64%) and 2 (14%) patients, respectively. As for late infectious complications, 7 patients (50%) developed dermatomal varicella zoster virus infection. No infection‐related mortality was seen in this case series. Because the risk for infections approaches that seen in allogeneic transplant recipients, infection surveillance, diagnostic workup, and prophylactic strategies similar to those applicable to allogeneic recipients are warranted.

Oral valganciclovir as preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients.

Between March 2007 and January 2008, the safety and efficacy of oral valganciclovir (VGC) preemptive therapy for cytomegalovirus (CMV) infection was evaluated in ten consecutive patients who received allogeneic hematopoietic stem cell transplantation (HSCT). Patients were screened once or twice per week after engraftment using CMV pp65 antigenemia assay. When more than 2 CMV antigen-positive cells per 50,000 leukocytes were detected, preemptive therapy with oral VGC was initiated at a dose of 900 mg twice daily for 3 weeks. Nine patients (90%) completed the 3-week VGC treatment except for one patient who developed febrile neutropenia. There was no other significant toxicity. CMV antigen-positive cells were rapidly decreased in all nine patients and became undetectable by the end of the VGC treatment. None of the patients developed CMV disease. CMV infection relapsed in four of the ten patients (40%) after the VGC treatment. These observations suggest that preemptive therapy with VGC is effective for preventing CMV disease in allogeneic HSCT patients. Further studies with a large number of patients will be necessary to determine the optimal initial- and maintenance-dose of VGC.