Yoshihisa Morishita

Osteonecrosis of the femoral head after allogeneic bone marrow transplantation.

A comparative retrospective analysis of 100 consecutive patients after bone marrow transplantation was performed with magnetic resonance imaging in addition to plain radiography for the development of osteonecrosis of the femoral head. The incidence and risk factors for osteonecrosis of the femoral head were identified, comparing various parameters concerning bone marrow transplantation between the groups with and without evidence of osteonecrosis. Nineteen (19%) of 100 patients had osteonecrosis of the femoral head develop. Four factors were found to be statistically significantly different between patients who had osteonecrosis develop and those who did not: younger age at the time of bone marrow transplantation, chronic graft-versus-host disease, cumulative dose of steroid, and intravenous pulse therapy with methylprednisolone. It was concluded that a low rate of complications and low dose steroid administration would reduce the incidence of osteonecrosis after bone marrow transplantation.

Solid tumors after hematopoietic stem cell transplantation in Japan : incidence, risk factors and prognosis

Summary:To evaluate the incidence, risk factors and prognosis for solid tumors after hematopoietic stem cell transplantation (HSCT) in Japan, 809 patients who had received HSCT between 1981 and 2000 were retrospectively analyzed. In all, 19 newly diagnosed secondary cancers were observed. The risk for cancer development was 2.8 times as high as that for expected cases. The cumulative incidence ratios at 5 and 10 years were 1.9 and 4.2%, respectively. The risk was significantly elevated for buccal cavity cancer (standard incidental ratio (SIR), 44.42: 95% confidence interval (CI) 17.86–91.51), esophageal cancer (SIR, 22.36: 95% CI 6.09–57.25), and cervical cancer (SIR, 8.58: 95% CI 1.04–31.01). Of 15 patients who developed solid cancers following allografting, 12 had chronic graft-versus-host disease (GVHD), and all 10 patients with squamous cell carcinoma of the buccal cavity or esophagus had chronic GVHD. On multivariate analysis, extensive chronic GVHD and age over 45 years at the time of transplantation were associated with a higher risk for solid cancers. In all, 17 patients received therapy for secondary cancers, nine of whom are still alive and the 5-year probability of survival from the diagnosis is 42.8%. Our data suggest that early detection of secondary cancers is very important in prolonging overall survival.

Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: Retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation

Summary:CMV disease remains a major infectious complication after allogeneic hematopoietic stem cell transplantation (HSCT). To investigate the relationship between CMV antigenemia, treatment with ganciclovir (GCV), and outcome, we retrospectively analyzed 241 consecutive patients at risk for CMV infection who underwent allogeneic HSCT. Antigenemia-guided pre-emptive strategy with GCV was used for all patients. CMV antigenemia developed in 169 patients (70.1%), and CMV disease in 18 patients (7.5%). Multivariate analysis showed that acute GVHD (grades II–IV) was the only risk factor for developing antigenemia, and acute GVHD and advanced age for CMV disease. GCV use, as well as acute GVHD and advanced age, significantly increased the risk for bacterial and fungal infection after engraftment. Those who developed CMV antigenemia had a poorer outcome than those who did not (log-rank, P=0.0269), although the development of CMV disease worsened the outcome with only borderline significance (log-rank, P=0.0526). In conclusion, detection of antigenemia proved to be a poor prognostic factor for HSCT patients, which may be attributed to a combination of factors, including CMV disease itself, the effect of treatment, and a host status that allows for reactivation of CMV. Optimal pre-emptive strategy needs to be determined.

Usefulness of Bone Marrow Aspiration for Definite Diagnosis of Asian Variant of Intravascular Lymphoma: Four Autopsied Cases

The Asian variant of intravascular lymphoma (AIVL) is characterized by hemophagocytic syndrome, pancytopenia and hepatosplenomegaly but usually lacks any neurological abnormality and skin lesions, which are typical features of classical intravascular lymphoma (IVL). An ante-mortem diagnosis of AIVL is difficult due to the absence of visible lymphoma lesions and unspecific clinical manifestations. A definite diagnosis relies on the presence of neoplastic B cells in the lumina of small vessels. Paraffin block samples of aspirated bone marrow clots were obtained from 4 patients with clinically suspected IVL and subjected to immunohistopathological analysis. All samples exhibited CD 20+ or CD 79a+ lymphoma cells proliferating intravascularly as well as erythrocytic hemophagocytosis. The distribution of neoplastic cells in the structure of the bone marrow allowed IVL to be distinguished from bone marrow invasions due to other types of lymphoma. We demonstrated the successful establishment of a definite ante-mortem diagnosis of AIVL in 3 of 4 patients by the rapid and simple method of using aspirated bone marrow samples.

Multiplex real-time RT-PCR for prospective evaluation of WT1 and fusion gene transcripts in newly diagnosed de novo acute myeloid leukemia

Prognostic assessment is crucial for the management of AML. Although the use of karyotype analysis for risk-stratification is widely accepted, prognosis of AML remains ambiguous, particularly for patients categorized into the intermediate cytogenetic risk group and additional markers are required for an accurate prediction of outcome. For this study, we used multiplex real-time RT-PCR, which can simultaneously quantify WT1 and 10 distinct fusion gene transcripts, to prospectively evaluate the pre-treatment bone marrow findings of 53 de novo AML patients. Five patients with normal karyotype or insufficient metaphases detected by conventional karyotype analysis proved to have AML1-MTG8, CBFbeta-MYH11 or PML-RARalpha fusion transcripts. WT1 overexpression was observed in 92% of the patients, and the levels were significantly higher in the cytogenetic favorable risk group, especially patients with PML-RARalpha. WT1 levels also correlated with the percentage of blasts in bone marrow, especially in cases of core-binding factor leukemia. There was no association between initial WT1 levels and outcome in terms of event-free survival or overall survival. These results suggest that multiplex real-time RT-PCR is rapid and useful for the precise cytogenetic stratification of AML, and that WT1 levels at presentation correlate with several biologic features of leukemia, but have no prognostic significance.

Clinical impact of graft-versus-host disease against leukemias not in remission at the time of allogeneic hematopoietic stem cell transplantation from related donors. The Japan society for hematopoietic cell transplantation working party

Summary:Acute graft-versus-host disease (GVHD) increases post-transplant mortality and morbidity, but exerts a potent graft-versus-leukemia (GVL) effect. To clarify the impact of GVHD on outcome after transplant in aggressive diseases, patients with acute myeloid or lymphoblastic leukemia (AML, n=366 or ALL, n=255) in nonremission states, or chronic myelogenous leukemia (CML, n=180) in accelerated phase (AP) or blastic crisis (BC), who received allogeneic hematopoietic stem cell transplantation (HSCT) from a related donor between 1991 and 2000, were analyzed. Significant improvement in overall and disease-free survival (DFS) was detected with grade I acute GVHD in AML (P=0.0002 for overall survival and 0.0009 for DFS, respectively) and in CML (P=0.0256 and 0.0366, respectively), while the trend towards improved survival was observed in ALL. Relapse rate was lower in grade I acute GVHD than in grade II in all three diseases, suggesting that treatment for grade II GVHD may compromise the GVL effect associated with GVHD. Chronic GVHD was found to suppress relapse in CML and ALL, but not in AML, although no improvement in survival was observed in any disease category. Our results suggest that treatment for grade II acute GVHD may need to be attenuated in transplant for refractory leukemias.

Treatment of plasma cell neoplasm with recombinant leukocyte A interferon and human lymphoblastoid interferon

SummaryThisty cases of plasma cell neoplasms (24 multiple myeloma, one plasma cell leukemia, and three primary macroglobulinemia) were treated with two kinds of highly purified α-interferons, recombinant human leukocyte interferon (rIFN-αA) (16 cases) and human lymphoblastoid interferon (HLBI) (14 cases). Partial remission (PR) was obtained in two of 16 evaluable cases treated with rIFN-αA and in two of 12 evaluable cases treated with HLBI. If minor response (MR) was included, responses were observed in seven (31.3%) and six (50%), respectively. Response (PR+MR) was noted in 38% of 21 previously treated patients and 71% of seven previously untreated patients. Side-effects were noted in more than two-thirds of the patients. They included fever, malaise, nausea/anorexia and myelosuppression. Thus, these two kinds of highly purified α-interferon were effective in plama cell neoplasm, producing unequivocal response in 14.3% of the cases without unacceptable side-effects.

Thalidomide for tocilizumab-resistant ascites with TAFRO syndrome.

TAFRO syndrome have been proposed as a rare variant of Castlemans disease. This article reports a case of a 56‐year‐old man with TAFRO syndrome who was successfully treated with thalidomide in spite of the refractoriness to prednisolone and tocilizumab. Thalidomide may be one of the treatment options for TAFRO syndrome.

Early central nervous complications after umbilical cord blood transplantation for adults.

Early central nervous complications (CNS) are significant after allogeneic stem cell transplantation; however, the clinical characteristics of early CNS complications have not yet been well described. The medical record of 77 patients who underwent cord blood transplantation (CBT) between March 2001 and November 2005, at 8 centers of the Nagoya Blood and Marrow Transplantation Group were retrospectively reviewed. The preparative regimen included myeloablative CBT (n = 31) or reduced-intensity (RI)-CBT (n = 46). Of the 77 patients, 10 (13%) developed early CNS complications. Causes included Cyclosporine encephalopathy (n = 5), tacrolimus encephalopathy (n = 2), thrombocytic microangiopathy (n = 1), and unknown (n = 3). The median time of onset was 19 days (range: 2-58 days). All of the 10 patients developed impaired consciousness. Seizures developed in 6 patients. Early CNS complications spontaneously subsided in 3 patients. Three patients responded to cyclosporine or tacrolimus discontinuation. The remaining 4 patients died within 30 days of developing of early CNS complications. No relationship was detected between the preparative regimen and the onset of early CNS complications, while an HLA disparity showed borderline significance (hazard ratio, 3.24; 95% confidential interval, 0.94-11.20; P = .06). Early CNS complications are a significant problem after CBT, and the clinician has to be aware of the possibility of these complications.

Current status of hematopoietic cell transplantation for adult patients with hematologic diseases and solid tumors in Japan.

A nationwide survey of hematopoietic cell transplantation (HCT) was started in Japan in 1991, and the analyzed survey data have been presented as the annual report of the Japan Society for Hematopoietic Cell Transplantation.The 10-year overall survival (OS) rates after HCT for each disease are as follows: acute myelogenous leukemia, 44.2%; acute lymphocytic leukemia, 33.7%; adult T-cell leukemia, 24.6%; chronic myelogenous leukemia, 53.3%; myelodysplastic syndrome, 37.3%; non-Hodgkin’s lymphoma, 41.5%; Hodgkin’s lymphoma, 50.8%; aplastic anemia, 72.5%; breast cancer, 37.1%; germ cell tumor, 52.6%; and ovarian cancer, 44.2%.The 5-year OS rates for multiple myeloma and lung cancer were 40.6% and 23.6%, respectively. Except in cord blood transplantation, engraftment was accomplished in more than 90% of patients.The respective frequencies of acute graft-versus-host disease (GVHD) and chronic GVHD were 41.1% and 34.9% for related bone marrow transplantation (BMT), 66.8% and 34.5% for unrelated BMT, 52.9% and 36.0% for allogeneic peripheral blood stem cell transplantation, and 53.3% and 32.1% for allogeneic cord blood transplantation. OS for each disease was analyzed by patient age, stem cell source, donor type, disease status, and disease type.These data provide objective and valuable information for hematologists as well as for patients who need HCT.