Efficacy and safety of intravenous itraconazole as empirical antifungal therapy for persistent fever in neutropenic patients with hematological malignancies in Japan.

Recently, empirical antifungal therapy with intravenous itraconazole (ITCZ) for neutropenic patients with antibiotics-resistant fever has been approved by Japanese Ministry of Health, Labour and Welfare on the bases of previous multicenter trials of foreign countries. In this study, we conducted a single-arm, multicenter, prospective study in order to evaluate the efficacy of empirical ITCZ injection on Japanese patients. Sixty-eight patients with hematological diseases who underwent anticancer chemotherapy or stem cell transplantation were enrolled. In this study, we found that the overall clinical response rate to ITCZ injection was 67.6% and success rate of achieving composite endpoints including survival, defervescence during neutropenia, no breakthrough fungal infections, and no premature discontinuation of drug was 50.0%. Mild adverse reactions were observed in 6 patients (8.8%). Further analysis revealed that possible/probable deep fungal infection according to the 2002 and 2008 criteria defined by EORTC/MSG were found in 19.1 and 7.5% of the patients, respectively. Interestingly, response rate to ITCZ injection of possible/probable cases according to the 2002 and 2008 criteria was 61.5% (8/13) and 100% (5/5), respectively. These results not only proved the good efficacy and safety of empirical ITCZ injection for Japanese patients, but also indicated a utility of the drug on future "presumptive" approach.

[High-dose chemotherapy with autologous hematopoietic stem cell transplantation for non-Hodgkin's lymphoma in complete response as consolidation therapy, second report].

High-dose chemotherapy followed by autologous peripheral blood transplantation (HD-APBSCT) is a therapeutic option for patients with non-Hodgkin's lymphoma (NHL) after complete remission (CR) as consolidation therapy. In this report we describe a retrospective study of such treatment. A total of 38 patients with NHL were treated between November 19 9 1 and March 2005. At five years,the rate of disease-free survival (DFS) and overall survival (OS) was 64.3% and 66.5%, respectively. Patients who underwent transplantation in first CR had a 5-year probability of disease-free survival of 71.6% compared with 35.7% for those who were in second CR at the time of transplantation (p=0.10). In a monovariate analysis, second CR status at the time of transplantation was a relatively adverse predictor of DFS. None of those factors containing surface markers were significantly associated with clinical variables such as the CR status at the time of transplantation. Thirty high intermediate risk and high risk patients with aggressive B-cell lymphoma had a better outcome than patients treated with standard chemotherapy. In this study, 8 patients with T-cell lymphoma had a 3-year DFS and OS of 87.5% and 87.5%, respectively. HDT-APBSCT is a candidate for consolidation therapy for high-intermediate risk and high risk patients with aggressive B-cell and T-cell lymphoma.

[Rituximab provided long-term remission in a patient with severe thrombotic thrombocytopenic purpura refractory to plasma exchange].

We report a patient with severe thrombotic thrombocytopenic purpura (TTP) refractory to plasmapheresis who was successfully treated with rituximab. A 57-year-old male patient was referred to our department for further differential diagnosis and treatment of anemia and severe thrombocytopenia. Progressive psychoneurotic symptoms, hemolytic anemia, thrombocytopenia, renal function insufficiency and fever led us to the diagnosis of TTP. ADAMTS13 activity was below 3% and an inhibitor for ADAMTS13 was detected. Treatment with plasmapheresis and high-dose steroid was initiated but without clinical benefit. Two weeks following the initiation of plasmapheresis, we decided to treat the patient with 7 cycles of rituximab. No severe rituximab-related adverse effects were observed. After treatment with rituximab, the disease remitted, and the ADAMTS13 activity level increased. The patient has remained in complete remission for more than 1 year. Our data suggest that rituximab may be the optimal immunosuppressive therapy for refractory thrombotic thrombocytopenic purpura caused by an anti-ADAMTS 13 inhibitor.

Conditioning regimens including high-dose busulfan cause a high incidence of transplant-related mortality after myeloablative stem cell transplantation.

BACKGROUND: Transplant-related mortality (TRM) significantly decreases the long-term survival of patients with hematopoietic diseases who undergo hematopoietic stem cell transplantation (HSCT). METHODS: We retrospectively evaluated the risk factors for TRM of 58 consecutive patients with hematopoietic disease who underwent allogeneic myeloablative HSCT between April 1994 and June 2002. RESULTS: Thirty-one patients died after HSCT, 16 of whom were diagnosed as TRM. The actuarial incidence of TRM was 57.6 % in patients who received conditioning chemotherapies including high-dose busulfan and 19.4 % in those who did not (p = 0.008). Multivariate Cox model analysis revealed that disease status, graft versus host disease (GVHD) grades III-IV and the use of high-dose busulfan were significant and independent risk factors for TRM. CONCLUSION: These results suggest that high-dose busulfan as a conditioning therapy for allogeneic HSCT should be used cautiously, especially in patients with advanced disease.

Pericarditis associated with Epstein-Barr virus reactivation in a patient following allogeneic peripheral blood stem cell transplantation from an HLA genotypic 1-locus mismatched sibling donor.

A 31-year-old woman with acute myeloblastic leukemia (AML) underwent allogeneic peripheral blood stem cell transplant (PBSCT). On day +274 following transplantation, the patient had severe chest pain, high-grade fever, and general fatigue. Electrocardiographic examination revealed ST segment elevation, and echocardiographic examination revealed an obvious pericardial. The diagnosis of pericarditis was made. We could not exclude the possibility of a combination of chronic GVHD involving the liver, because biochemistry examination revealed altered liver dysfunction, but liver biopsy was not performed. The patient underwent empirical treatment for bacterial or viral infection, and was given prednisolone for chronic GVHD. Retrospective serologic examination revealed that EBV reactivation had occurred at this time. This is the first reported case of pericarditis associated with EBV reactivation after allogeneic-stem cell transplantation (allo-SCT).

[MR imaging provides important clues for the diagnosis of benign intracranial hypertension by all-trans retinoic acid in a patient with acute promyelocytic leukemia].

We report a case of benign intracranial hypertension (BIH) caused by all-trans retinoic acid (ATRA) in a patient with acute promyelocytic leukemia. A 21-year-old male was admitted to our hospital with pancytopenia. He was diagnosed as having acute promyelocytic leukemia due to increased promyelocytes, and PML-RAR alpha chimeric mRNA was detected. The administration of ATRA and idarubicin was started immediately. After 26 days of the chemotherapy, he complained of diplopia. Ophthalmologic examination revealed bilateral papilledema and hemorrhage. The cerebrospinal fluid showed an increase in pressure, but no other abnormalities. Computed tomography showed no intracranial abnormalities. The orbital MR imaging showed distension of the perioptic subarachnoid space and flattening of the posterior sclera. A diagnosis of BIH was made. After the discontinuation of ATRA, the symptoms improved and the MR abnormalities disappeared. As far as we know, there have been no reports illustrating MR abnormalities of BIH caused by ATRA, for the diagnosis and monitoring of which orbital MR imaging can provide important clues.

[Salvage combination chemotherapy with cytarabine, carboplatin and steroids for relapsed or refractory non-Hodgkin's lymphoma].

We have treated 29 patients (19 men and 10 women) with relapsed or refractory non-Hodgkin's lymphoma with a combination of cytarabine (Ara-C), carboplatin (CBDCA) and prednisolone (PSL). The regimen, on days 1 to 3, included Ara-C, 400 mg/m2 i.v.; CBDCA; 250 mg/m2 i.v.; and PSL, 40 mg/m2. Since complete response was achieved in 10 patients (34.5%) and partial response in 9 (31.0%), the total response rate was 65.5%. The 50% survival duration of all patients after the initiation of this therapy was 8 months. The overall 5-year survival rate was 66.7% for those who achieved CR or PR with the Ara-C/CBDCA regimen and received high-dose chemotherapy and autologous hematopoietic stem cell transplantation. Myelosuppression was the major toxicity. Total WBC counts under 1,000/microliter were seen in 67.7% of the courses, and thrombocytopenia under 50,000/microliter was seen in 96.8%. Ara-C/CBDCA has proven to be an effective salvage regimen for patients with relapsed or refractory lymphoma. High-dose chemotherapy and autologous hematopoietic stem cell transplantation should be considered for salvageable patients.

A case of a long-time survivor with chronic active Epstein-Barr virus infection.

Epstein-Barr virus (EBV) is associated with hypersensitivity to mosquito bites (HMB) and fatal EBV-associated hemophagocytic syndrome (HPS). The prognosis of patients with chronic active EBV infection (CAEBV) is very poor. We report a rare case of an adult woman patient with a 28-yr history of HMB, who developed EBV-HPS. EBV genome was detected in the serum and peripheral blood lymphocytes. Clonal proliferation of EBV was demonstrated by Southern blot analysis using an EBV genome terminal-repeat probe. This is a very rare case of a long-term survivor with CAEBV. The patient was initially treated with immunochemotherapy and achieved complete remission. However, the patient immediately relapsed and underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched brother. Peripheral blood cell recovered well, and EBV genome disappeared from the peripheral blood. Allogeneic BMT may be effective in eradicating EBV-HPS. Unfortunately, the patient died of graft vs. host disease on the 92nd day after BMT.

Reduced-intensity stem cell transplantation in two cases of metastatic renal cell carcinoma.

Allogeneic hematopoietic stem-cell transplantation can induce curative graft-versus-leukemia reactions in patients with hematological malignancies. There is also evidence of such an effect in patients with solid tumors. We report two patients with metastatic renal cell carcinoma who underwent RIST. In both patients, disease progression was observed 6 months after transplantation. However, one patient had transient symptoms of tumor progression after the occurrence of acute graft-versus-host disease, consistent with graft-versus-tumor effects.

[Successful treatment with foscarnet for disseminated varicella-zoster infection after reduced intensity stem cell transplantation in a case of relapsed refractory central nervous system lymphoma].

Visceral disseminated varicella-zoster virus (VZV) infection occurred with acute graft-versus-host disease in a 33-year-old Japanese male with non-Hodgkin lymphoma who had undergone allogeneic stem cell transplantation from an HLA-identical sibling after reduced intensity conditioning chemotherapy. Although ganciclovir and acyclovir treatment was effective temporarily, the number of VZV-DNA copies in the blood remained at a high level, and the hepatitis was prolonged. The patient was treated with foscarnet, which led to improvement of the VZV viremia and the hepatic dysfunction. Foscarnet therapy should be considered for acyclovir-resistant VZV infection in the setting of allogeneic hematopoietic stem cell transplantation.

[Analysis of factors for poor mobilization after administration of recombinant human granulocyte stimulating factor (rHuG-CSF) in healthy donors].

Allogeneic hematopoietic stem cell transplantation is an effective treatment for hematological malignancies. Peripheral blood stem cells (PBSCs) are increasingly used as an alternative to bone marrow for allogeneic transplantation. However, predictive factors for the response to recombinant human granulocyte stimulating factor (rHuG-CSF) in healthy donors have not been extensively studied. We analyzed the side effects, laboratory test results after administration of rHuG-CSF and the factors influencing mobilization of peripheral blood stem cells in 30 healthy donors. Bone pain, fever and headache were observed with high frequency after administration of rHuG-CSF. WBCs and reticulocytes increased, and RBCs and platelets decreased significantly after administration rHuG-CSF. Biochemical examination revealed significant elevations of LDH, CRP, ALP and UA. Univariate analysis showed the age of donors (< 50 vs. > 50, p = 0.041) and the lymphocyte counts before administration of rHuG-CSF (p = 0.032) to be correlated with the number of CD34 positive cells. From a multivariate analysis, the tendency for good mobilization with a twice daily dose of rHuG-CSF (p = 0.065) was observed. The rHuG-CSF schedule may be the most important factor affecting peripheral blood stem cell mobilization and collection in healthy donors.

Development of chronic myelocytic leukemia after chemotherapy for malignant fibrous histiocytoma.

At the age of 28, a 33-year-old male was diagnosed with malignant fibrous histiocytoma (MFH) with a primary lesion in the right maxillary sinus. Although arterial infusion chemotherapy (pirarubicin hydrochloride and carboplatin) was given, no tumor shrinkage was observed, and surgery was therefore performed to remove the tumor. Thereafter, the patient received autologous peripheral blood stem cell transplantation with high-dose chemotherapy (combination of ifosphamide, carboplatin and etoposide) as pretreatment. An increase in the peripheral leukocyte count was noted 56 months after the diagnosis of MFH was made. Cytogenetic study showed translocation (9;22)(q34;q11). Chronic myelocytic leukemia (CML) was therefore diagnosed. MFH was in a state of complete remission. The clinical course of this patient strongly suggests that this was a case of treatment-related CML that developed after chemotherapy for MFH. Treatment-related malignant blood diseases are known to include acute myelocytic leukemia and myelodysplastic syndrome, but reports of treatment-related CML are rare, although there have been some cases of treatment-related CML occurring several years after pretreatment.

Automatic analysis of normal bone marrow blood cells using the XE-2100 automated hematology analyzer.

The bone marrow aspiration test conventionally has been performed by visual methods, using a light microscope, because automatic blood cell analyzers cannot adequately capture erythroblasts and immature granulocytes (IGs) (Tatsumi et al.: Osaka City Med J 1988;34:135-146; Tatsumi et al.: Am J Clin Pathol 1986;86:50-54). With the development of the XE-2100 automatic blood cell analyzer (Sysmex Corporation, Kobe, Japan) in 1999, the classification of erythroblasts and IGs by means of flow cytometry (Zini et al.: Infus Ther Transfus Med 2001;28:277-279; Briggs et al.: Sysmex J Int 1999;9:113-119) became possible. In the present study we classified cells in 65 bone marrow aspiration specimens by the microscopic method and with the XE2100, and compared the results. A good correlation was found in the nucleated red blood cell (NRBC), white blood cell (WBC), and total nucleated cell (TNC) counts; the myeloid/erythroid ratio (M/E ratio); neutrophils, lymphocytes, eosinophils, and IGs in the immature myeloid information (IMI) channel; and the total cell count. These items can all be analyzed in about 54 sec with the XE2100, which is faster than with the microscopic method. Therefore, analysis of bone marrow aspiration specimens with this apparatus appears to be very useful for clinical screening as well as laboratory testing.

Infliximab for the treatment of severe steroid refractory acute graft-versus-host disease in three patients after allogeneic hematopoietic transplantation.

Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic peripheral blood stem cell transplantation (PBSCT). Patients with severe aGVHD not responding to treatment with steroids have a poor prognosis. We treated three patients with severe aGVHD refractory to steroids with infliximab. Patients (MDS 1, NHL 1, ALL 1) developed grade II-IV GVHD at a median of 13 days (range 9-17) after non-myeloablative PBSCT (HLA mismatched). All patients had received treatment with high-dose steroids for a median of 7 days (range 7-10) in addition to mycophenolate mofetil (MMF) (one). Infliximab was given in 3 weekly doses of 5 mg/kg. In one of three patients a partial resolution of diarrhea and minor improvement of skin were observed. One patient died with refractory GVHD. Infliximab is apparently an effective drug for the treatment of aGVHD, but can be more effective at doses of 5 mg/kg or higher and/or by administering it repeatedly every week.

[Chronic myelogenous leukemia treated with non-myeloablative stem cell transplantation after discontinuing myeloablative stem cell transplantation due to mental aberrations].

A 54-year-old woman with chronic myelogeneous leukemia was admitted to our hospital on February 15th, 2001 to undergo allogeneic bone marrow transplantation (BMT). We started the transplantation preconditioning with busulfan and high-dose cyclophosphamide on February 22nd, 2001. However, symptoms of a psychiatric nature, such as hallucination, persecution complex, auditory hallucination and sleeplessness, occurred by the third day of treatment with busulfan. Thus, we decided to discontinue conditioning and stopped the administration of BMT at that point. However, pancytopenia persisted for more than 20 days. She finally underwent BMT followed by reduced-intensity conditioning with fludarabine and ATG from a sex-mismatched, HLA-identical sibling donor on April 19th, 2001. To prevent any exacerbation of the psychotic symptoms, the patient was hospitalized in a laminar flow instead of a bio-free room. Graft-versus-host disease occurred on the 32nd hospital day, and was brought under control by steroid treatment. Achievement of complete chimeras was confirmed on the 54th hospital day. Her mental condition was kept stable with antidepressant drugs and tranquilizers, although minor changes in the combination of drugs were required to treat transient exacerbation of psychosis after a short period at home. She was discharged on September 1st, 2001. We think that non-myeloablative stem cell transplantation is a useful treatment for patients with hematological malignancy complicated with psychiatric disorders.

Possible automatic cell classification of bone marrow aspirate using the CELL-DYN 4000 automatic blood cell analyzer.

In clinical hematology, the demand for bone marrow aspiration testing is increasing. However, conventional automatic blood cell analyzers cannot completely analyze erythroblasts, and evaluation has mainly been performed by visual examination (the microscopic method). Using the CELL-DYN 4000 automatic blood cell analyzer (CD4000) (Abbott Laboratories, North Chicago, IL), specific recognition and classification of erythroblasts by DNA staining is possible. In the present study, using bone marrow blood collected from normal subjects and patients with hematological malignancy, we classified cells by the microscopic method and with the CD4000, and compared the results. Good correlations were found for total nucleated cell count (TNCC), neutrophils, lymphocytes, erythroblasts, and the myeloid series to erythroid series (M/E) ratio. It is possible to detect blasts that emerge in patients with hematological malignancy using the blast flag system installed on the CD4000. Since all of the items can be analyzed in about 80 sec with the CD4000, cells in bone marrow aspirates can be classified faster with this apparatus than by the microscopic method. Therefore, analysis of bone marrow aspirates with this apparatus appears to be very useful not only for laboratory testing but also for clinical screening.