Allogeneic myeloablative transplantation for patients aged 50 years and over.

Allogeneic hematopoietic stem cell transplantation (HSCT) has been performed mainly for young patients due to concern about the high incidence of treatment-related mortality (TRM). Recent advances to reduce TRM by using peripheral blood stem cells or nonmyeloablative conditioning regimens have increased the age limit for this procedure, and correctly identifying the indication for transplant is essential for older patients. In this study, we analyzed data from 398 patients aged 50 or over selected from 5147 patients, who received conventional allogeneic HSCT (c-HSCT). Patients aged 50 or older showed inferior outcomes for TRM and overall survival (OS). Mulitivariate analyses confirmed that an age of 50 or over was an independent risk factor for TRM (P<0.0001) and OS (P<0.0001). Among patients aged 50 or older, increasing age remained an adverse factor for OS (P=0.0213). Regimens including total-body irradiation (TBI) correlated with a higher risk of TRM and a lower OS for older patients (P=0.0095 and 0.0303, respectively). These findings indicate that allogeneic c-HSCT should be offered to patients over 50 years only if the increased risk of TRM is acceptable, and that a non-TBI regimen is preferable when the transplant is performed.

[Requirements for early discharge after allogeneic bone marrow transplantation].

To assess the requirements for early discharge after allogeneic bone marrow transplantation (BMT), we evaluated infectious complications and transplantation-related toxicity (TRT) among 46 recipients who underwent allogeneic BMT between January 1997 and August 1999 at our institute. Acute graft-versus-host disease (GVHD) and cytomegalovirus (CMV) antigenemia developed in 29 and 26 patients, respectively. More than 95% of the episodes occurred before day 70. Among the patients without CMV antigenemia and without prednisolone (PSL) therapy for acute GVHD (n = 15), only 3 developed TRT or infections (pneumonia, varicella zoster virus infection and hemolytic uremic syndrome), but all of these episodes were cured without fatality. On the other hand, in patients with CMV antigenemia and/or PSL therapy for acute GVHD, a high incidence of TRT and infectious complications was observed until day 180, and some of these episodes were fatal. In conclusion, discharge on day 70 after allogeneic BMT seems to be safe for patients who do not develop CMV antigenemia or receive PSL therapy for acute GVHD.

Late onset cyclosporine-induced cerebral blindness with abnormal SPECT imagings in a patient undergoing unrelated bone marrow transplantation.

A 23-year-old woman underwent HLA-matched unrelated BMT for CML. She developed cerebral blindness on day 81. Brain magnetic resonance imaging revealed hyperintensity on a T2-weighted image in the white and gray matter of the right frontal and both occipital lobes. Single-photon emission computed tomography (SPECT) was consistent with a decrease in radionuclide uptake in these areas, suggesting a vasoconstrictive mechanism. A diagnosis of CsA-induced encephalopathy was made and CsA was discontinued. Her vision recovered completely after 24 h and abnormal imaging resolved within 2 weeks. This case demonstrates late onset CsA-induced cerebral blindness with the previously unreported abnormalities on SPECT.

Serum levels of soluble IL-2 receptor, IL-12, IL-18, and IFN-gamma in patients with acute graft-versus-host disease after allogeneic bone marrow transplantation.

BACKGROUND: Acute graft-versus-host disease still represents the major factor that limits successful allogeneic bone marrow transplantation. Cytokines released by type 1 T-helper cells are thought to play a pivotal role in acute graft-versus-host disease. OBJECTIVE: This study was performed to investigate whether the serum levels of soluble IL-2 receptor, IL-12, IL-18, and IFN-gamma were associated with the manifestation of acute graft-versus-host disease. METHODS: Serum cytokine levels were measured by sandwich ELISA in 18 patients who underwent allogeneic bone marrow transplantation. RESULTS: Serum levels of soluble IL-2 receptor, IL-12, IL-18, and IFN-gamma were increased in patients in whom acute graft-versus-host disease developed. However, only serum soluble IL-2 receptor levels were significantly related to disease severity. Serum levels of IL-12 and IL-18, both of which are mainly produced by activated macrophages, were increased in different phases of acute graft-versus-host disease, especially grade I. Serum levels of soluble IL-2 receptor and IFN-gamma were significantly elevated in patients with fever. CONCLUSION: Serum levels of soluble IL-2 receptor were more closely related to the severity of acute graft-versus-host disease than those of IL-12, IL-18, and IFN-gamma.

Acute abdomen without cutaneous signs of varicella zoster virus infection as a late complication of allogeneic bone marrow transplantation: importance of empiric therapy with acyclovir.

Two patients complained of severe abdominal pain as the first sign of varicella zoster virus infection about 1 year after allogeneic BMT. In case 1, eruptions, found on the face and chest on admission, became vesicular and dispersed on the third hospital day. Though acyclovir (ACV) was immediately started, he died on the fourth day. In case 2, skin rash was never observed during the clinical course. Laparotomy on the third hospital day revealed many hemorrhagic spots on the liver surface and mucous membrane of the upper GI tract, indicating disseminated visceral disease. Empiric therapy with ACV was successful.

Successful bone marrow transplantation in an adult patient with reactive hemophagocytic syndrome associated with myelodysplastic syndrome.

We report an adult case of reactive hemophagocytic syndrome (RHS) associated with myelodysplastic syndrome (MDS) who received emergency bone marrow transplantation (BMT). Despite methylprednisolone pulse therapy, high-dose gamma-globulin, and chemotherapy containing etoposide, the pancytopenia progressed. After informed consent, the patient underwent syngeneic BMT using melphalan as the conditioning regimen. The patient has been well without relapse of RHS and MDS for more than 2 years after BMT. This result suggests that the above strategy, including BMT, should be considered for the treatment of adult RHS associated with hematological malignancy.

Differences between lymphocyte subsets, after allogeneic bone marrow transplantation, in patients who received tacrolimus and patients who received cyclosporin A.

The subsets of peripheral blood lymphocytes after allogeneic bone marrow transplantation were compared in 20 patients who received tacrolimus and 34 patients who received cyclosporin A (CsA) prophylactically. The phenotypes of CD3, CD4, CD8, and D8/CD57 were analyzed by flow cytometry. The percentage of CD3+ cells in the tacrolimus group (58.8% +/- 21.6%) was significantly lower than in the CsA group (77.2% +/- 12.8%) (P = .0239). The percentage of CD8+CD57+ cells in the patients receiving tacrolimus and developing acute graft-versus-host disease (GVHD) (grade I, 20.1% +/- 10.6%; grade II-IV, 13.2% +/- 6.3%) was significantly higher than in the patients receiving CsA and developing acute GVHD (grade I, 10.7% +/- 5.2%; grade II-IV, 7.7% +/- 4.0%) (grade I, P = .0036; grade II-IV, P = .0255). The absolute number of CD8+CD57+ cells in the patients with grade II-IV acute GVHD was also significantly higher in the tacrolimus group compared with the CsA group. There was no difference in the incidence of acute GVHD in the 2 groups. Recovery from acute GVHD in the tacrolimus group (16.6 +/- 13.6 days) was more rapid than in the CsA group (30.8 +/- 24.8 days) (P = .0124). These results suggest that, compared with CsA, tacrolimus administered prophylactically induces more CD8+CD57+ lymphocytes when acute GVHD occurs and accelerates the recovery from acute GVHD more rapidly.

[Preservation, thawing and infusion of hematopoietic stem cells].

Peripheral blood stem cells can be stored by the following 3 methods: liquid storage, non-rate controlled freezing and rate controlled freezing. Methods of processing of these cells including thawing, ex vivo purging and infusion are described in detail.

Induction of autologous graft-versus-host disease after autologous peripheral blood stem cell transplantation.

BACKGROUND: Autologous graft-versus-host disease has been reported after the administration of cyclosporine in patients who have received autologous bone marrow transplantation. OBJECTIVE: The purpose of this study was to determine whether autologous graft-versus-host disease could be induced in recipients of autologous peripheral blood stem cell transplantation and whether tacrolimus induced the disease instead of cyclosporine. METHODS: Twelve patients with acute leukemia and 5 patients with malignant lymphoma received either cyclosporine (1 mg/kg/day) or tacrolimus (0. 05 mg/kg/day) orally after autologous bone marrow or peripheral blood stem cell transplantation. RESULTS: Autologous graft-versus-host disease of the skin, confirmed by histopathologic criteria, occurred in 40% of the patients at 8 to 25 days after transplantation and lasted 3 to 15 days. The frequency of autologous graft-versus-host disease was approximately the same (40%) irrespective of the source of the graft (bone marrow cells or peripheral blood stem cells) and the drug used for induction (cyclosporine or tacrolimus). CONCLUSIONS: This pilot study suggests that autologous graft-versus-host disease can be induced in recipients of autologous peripheral blood stem cell transplantation by cyclosporine or tacrolimus.

[New quinolone versus vancomycin/tobramycin for intestinal sterilization in patients who undergo allogeneic bone marrow transplantation].

The frequency of infection in recipients of allogeneic bone marrow transplants (BMT) who received oral new quinolones (NQ) was compared with that in BMT recipients who were given oral vancomycin/tobramycin (V/T). Between 1984 and 1997, our hospital treated 79 patients with V/T and 90 patients with NQ. Number of febrile days, duration of intravenous antibiotics administration, and frequency of documented infections were statistically the same for both groups. However, the frequency of grampositive bacterial infections, especially staphylococcal infections, was slightly higher in patients receiving NQ than in patients receiving V/T (p = 0.12). Of the patients who received NQ, those who underwent unrelated donor BMT procedures were generally febrile for slightly longer periods than those who underwent related donor BMT procedures (p = 0.10). These results suggest that oral NQ is as effective as oral V/T for the prevention of serious gramnegative bacterial infections in patients who undergo BMTs.

Effect of the interaction between fibronectin and VLA-4 on the proliferation of human B cells, especially a novel human B-cell line, OPM-3.

Very late antigen (VLA)-4 integrin has been suggested to play an important role in haemopoiesis. However, little is known concerning the roles of the fibronectin (FN)/VLA-4 interaction in the proliferation of human B cells. In this study we investigated the effect of immobilized FN on the proliferation of various B-cell lines, including a newly-established B-cell line, OPM-3, and human tonsillar B cells, that primarily express VLA-4 but not VLA-5. Immobilized FN significantly promoted the proliferation of OPM-3 cells and normal B cells via VLA-4. The cross-linking of beta1 integrins of OPM-3 cells resulted in the phosphorylation of the focal adhesion kinase (FAK) associated 90 kD protein, an increase in FAK-associated kinase activity, and the phosphorylation of Raf-1. Furthermore, the MEK1 inhibitor, PD98059, inhibited the FN-promoted proliferation of OPM-3 cells. These results demonstrate that the FN/VLA-4 interaction transmits the growth signal(s) which may be mediated by Ras pathway in OPM-3 cells, and suggest that OPM-3 cells may be of great value in studying the roles of the FN/VLA-4 interaction in human B-cell growth.

[Background and prognostic factors of fungemia in patients with hematological disease].

Sixty-two episodes of fungemia which occurred in patients with hematological disorders between 1976 and 1996 in our hospital were analyzed with respect to background and prognostic factors. Forty-four of the patients were male and 18 were female. The underlying diseases were acute leukemia in 36 cases, chronic myelogenous leukemia in 9, malignant lymphoma in 9 and others in 8 cases. Trichosporon beigelii and Candida tropicalis were the most frequently isolated fungal pathogens. The prevalence of C. crusei increased while that of C. albicans decreased after 1988. Fuungemia frequently occurred in patients with following factors: 1) advanced disease, such as relapse of acute leukemia or malignant lymphoma or blast crisis of chronic myelogenous leukemia; 2) neutrophil count less than 100/microliter; 3) administration of antibiotics; 4) focal infection, gastrointestinal hemorrhage or urinary catheterization; and 5) isolation of causative organisms from surveillance cultures obtained just before the onset of fungemia. The mortality rate of patients with fungemia was 74%. Absence of hypotension, increased neutrophil count for a week after the onset of fungemia, and the intravenous administration of Amphotericin B (AMPH) were good prognostic factors. Fungemia frequently occurred in patients with advanced disease and had a very poor prognosis. These results emphasized the importance of isolation of fungus from surveillance cultures, early initiation of AMPH administration, and attempts to increase neutrophil counts with G-CSF and other measures for improving the prognosis of fungemia in patients with hematological disorders.

[Remarkable increase of CD8+ CD11a+ and CD8+ CD57- T cells in patients with post-transfusion graft-versus-host disease].

We analyzed the distribution of two T cell subsets, CD8+ CD11a+ (CD8+ cytotoxic effector population) and CD8+ CD57- cells, in the peripheral lymphocytes of 3 post-operative patients with post-transfusion graft-versus-host disease (PT-GVHD) and 5 post-operative patients without PT-GVHD. The percentage of CD8+ CD11a+ cells in the PT-GVHD-negative control was 19 +/- 4%, and in the 3 patients with PT-GVHD, 69%, 66%, and 59%, respectively. The percentage of CD8+ CD57- cells in the PT-GVHD-negative control was 19 +/- 6%, and in the 3 PT-GVHD patients, 59%, 58%, and 55%, respectively. Significantly higher proportions of the two T cell subsets were consistently observed in the patients with PT-GVHD than in the PT-GVHD-negative control. These results suggest that the analysis of CD8+ T cell subsets may be useful for the simple and rapid laboratory diagnosis of PT-GVHD.

Vidarabine therapy for virus-associated cystitis after allogeneic bone marrow transplantation.

We describe a method of diagnosing virus-associated cystitis after allogeneic bone marrow transplantation (BMT) and treatment with vidarabine therapy. At 7-10 days post-BMT when cystitis was suspected, we observed urinary sediments by the Papanicolaou stain to detect virus inclusion bodies. When positive, we examined urinary sediments by transmission electron microscope and measured the diameter of viral particles to determine the families. This process needed only 4 days. Among 16 consecutive cases, adenovirus and polyomavirus were each detected in three. Adenovirus caused hemorrhagic cystitis in two cases and cystitis without macroscopic hematuria in one case. Polyomavirus caused cystitis without macroscopic hematuria in one case. Polyomavirus was also detected in two cases without any symptoms. Vidarabine (10 mg/kg/day i.v.) was administered for 5 days as one course. Soon after one course of vidarabine, most symptoms subsided and virus inclusion bodies disappeared in all cases except for one with severe hemorrhagic cystitis. From these experiences, vidarabine reduces excretion of adenovirus and polyomavirus in the urine of BMT recipients and improves clinical symptoms in some cases of cystitis associated with these viruses.

Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid.

Differentiation therapy with all-trans retinoic acid (ATRA) has marked a major advance and become the first choice drug in the treatment of acute promyelocytic leukemia (APL). However, patients who relapse from ATRA-induced complete remission (CR) have difficulty in obtaining a second CR with a second course of ATRA therapy alone. We tested the efficacy of a new synthetic retinoid, Am80, in APL that had relapsed from CR induced by ATRA in a prospective multicenter study. Am80 is approximately 10 times more potent than ATRA as an in vitro differentiation inducer, is more stable to light, heat, and oxidation than ATRA, has a low affinity for cellular retinoic acid binding protein, and does not bind to retinoic acid receptor-gamma. Patients received Am80, 6 mg/m2, orally alone daily until CR. Of 24 evaluable patients, 14 (58%) achieved CR. The interval from the last ATRA therapy was not different between CR and failure cases. The clinical response was well correlated with the in vitro response to Am80 in patients examined. Adverse events included 1 retinoic acid syndrome, 1 hyperleukocytosis, 9 xerosis, 8 cheilitis, 16 hypertriglyceridemia, and 15 hypercholesterolemia, but generally milder than those of ATRA, which all patients had received previously. Am80 is effective in APL relapsed from ATRA-induced CR and deserves further trials, especially in combination with chemotherapy.

[A case of Tsutsugamushi disease as an imported infection].

Tsutsugamushi disease is widely spread throughout Japan. A case of tsutsugamushi disease was seen in October, 1996. A 64-year-old male developed typical symptoms of tsutsugamushi disease with Rickettsia tsutsugamushi, after he returned to Japan from Cheju Island, Korea. Not only in Japan but also in other Asian countries including Korea, China, Taiwan, and Thailand, tsutsugamushi disease is one of the most important rickettsial diseases carried by ticks or mites. If a traveller returning from an Asian country has symptoms such as high fever, skin eruption, and lymphadenitis, we should suspect that he is suffering from tsutsugamushi disease and should search if he has an eschar on any area of his body. We should not forget that tsutsugamushi disease is an imported disease. Patients of tsutsugamushi disease often have hematological disorders. They are sometimes referred to the hematological section of the hospital. Hematologists should be familiar with this disease.

Autologous graft-versus-host disease.

Treatment with cyclosporine A, a prototypic immunosuppressive drug, following autologous bone marrow transplantation (autoBMT) induces autologous graft-versus-host disease (autoGvHD), similar to acute GvHD after allogeneic BMT. The development of autoGvHD appears to be associated with the emergence of autoreactive T cells recognizing self MHC class II antigens and the elimination of a T-cell-dependent peripheral autoregulatory mechanism. The induction of autoGvHD may be of benefit to the autoBMT patients by providing the graft-versus-tumor effect.

Simple diagnosis of graft-versus-host disease.

BACKGROUND: Among patients undergoing allogeneic bone marrow transplantation, we previously detected an increase of CD8+S6F1+ and CD8+CD57- cells with the onset of acute graft-versus-host disease. OBJECTIVE: This study was an attempt to develop a simple laboratory test for graft-versus-host disease. METHODS: We analyzed the percentage of the two lymphocyte subsets in the peripheral blood mononuclear cells of healthy volunteers, patients with posttransfusion graft-versus-host disease, and recipients of allogeneic bone marrow transplants. RESULTS: Two patients with posttransfusion graft-versus-host disease showed a high percentage of both subsets. When the graft-versus-host disease pattern was defined as 45% or more CD8+S6F1+ cells and 35% or more CD8+CD57- cells, it was found in none of 17 recipients without acute graft-versus-host disease, 9 of 16 recipients with grade I disease, and 8 of 9 recipients with grade II or worse disease had this pattern. CONCLUSIONS: Our test may be useful for the laboratory diagnosis of acute graft-versus-host disease.

Functional role of cation-independent mannose 6-phosphate/insulin-like growth factor II receptor in cell adhesion and proliferation of a human myeloma cell line OPM-2.

The molecular mechanism underlying the interaction between myeloma cells and stromal cells was investigated by using a human myeloma cell line (OPM-2) and human umbilical vein endothelial cells (HUVECs). Adhesion of OPM-2 cells to HUVECs was found to be significantly augmented with treatment of OPM-2 cells with an alpha-glycosidase inhibitor, castanospermine (CSP). The treatment of OPM-2 cells with CSP resulted in alteration of oligosaccharide structures of cell surface glycoproteins particularly at molecular weight of 220 kD (GP220). To determine if GP220 was involved in the adhesion of OPM-2 cells to HUVECs, cell surface glycoproteins of HUVECs were labeled by biotin and were incubated with the PVDF membrane to which cell surface glycoproteins of OPM-2 cells were blotted. The biotinylated glycoproteins at the plasma membrane of HUVECs specifically bound to GP220 of OPM-2 cells. Purification and partial amino acid sequencing of GP220 revealed that GP220 had a structure homologous to cation-independent mannose 6-phosphate/insulin-like growth factor-II (CIM6P/IGF-II) receptor. Furthermore, an antibody against CIM6P/IGF-II receptor was reactive with GP220, indicating that GP220 was a CIM6P/IGF-II receptor. The adhesion of OPM-2 cells to HUVECs was inhibited by mannose 6-phosphate. Moreover, M6P was found to suppress the adhesion of human myeloma cell lines, OPM-2 and RPMI 8226, to bone marrow stromal cells that was established from the patients with multiple myeloma. In addition, proliferation of OPM-2 was stimulated in response to IGF-II. These results suggest that CIM6P/IGF-II receptor may be functional in terms of supporting cell adhesion and proliferation of myeloma cells.

[Septicemia associated with hematopoietic disorders and its features according to respective primary disorders].

Two hundred eighty-seven episodes of septicemia which occurred in patients with hematological disorders between 1980 and 1993 were examined according to respective underlying diseases. The diagnosis of acute myelogenous leukemia (AML) was made in 155 patients, acute lymphocytic leukemia (ALL) in 45, chronic myelogenous leukemia (CML) in 29, malignant lymphoma in 36, adult T-cell leukemia (ATL) in 7, multiple myeloma (MM) in 8 and aplastic anemia (AA) in 7. Three hundred and two strains were isolated from 287 patients. Fifty two point three percent of the total isolates were gram-negative bacilli, 26.8% were gram-positive cocci, 17.2% were fungi and 3.6% were anaerobic bacteria. In ALL patients gram-positive cocci accounted for 42.0%. This rate was significantly higher than in other disorder. Additionally, oral mucositis or gingivitis was evaluated as clinical background in 36.1% of ALL cases. Forty-seven point two percent of organisms which caused septicemia in ALL patients were isolated from surveillance cultures of the throat just before the onset of septicemia. These data suggested that in ALL cases microbiological organisms more frequently invaded through injuries of oral mucosa. In ATL, CML, MM and AA patients, fungi accounted for more than 25% of causative organisms. The most common organism of all of the strains was Pseudomonas aeruginosa (21.9%), but in ATL and MM patients Escherichia coli was more common than P. aeruginosa. At the onset of the septicemia, neutrophil counts were less than 100/mm3 in 76.6% of all patients, and more than 3,000/mm3 in only 5.0%. In contrast to this result, in 66.7% of ATL patients and 37.5% of MM patients, septicemia occurred even when neutrophil counts were more than 3,000/mm3. Septicemia occurred in 28.2% of the total patients but died. The mortality rate in MM and AA patients (50.0% respectively) was higher than in other diseases. According to the mortality of each causative organisms, fungal septicemia had a terribly high mortality of 82.9% while other bacterial mortality was about 20%.