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We hypothesized that reducing the dosage of prophylaxis for graft-versus-host disease (GVHD) would reduce the risk of relapse and toxicity after bone marrow transplantation (BMT) from human leukocyte antigen (HLA)-identical siblings. In a prospective phase II trial, 21 patients with leukemia and myelodysplastic syndrome underwent BMT from HLA-identical siblings and received GVHD prophylaxis consisting of low-dose (1.5 mg/kg per day) cyclosporin A (CSP) with short-term methotrexate (MTX) treatment. This low-dose group was compared with a group of retrospective control patients (n = 22) who received a standard CSP dosage (3.0 mg/kg per day) and MTX. One patient died of transplantation-related causes within 100 days. The regimen-related toxicity was quite tolerable. Although acute GVHD of grades II to III was more frequent in the low-dose group (47.6%) than in the control group (22.7%), the increase in acute GVHD did not significantly contribute to morbidity or mortality. There were no differences between the groups in the incidence and severity of chronic GVHD. The probabilities of relapse and survival of the groups were similar according to the risk for relapse at the time of transplantation. A prospective randomized study is required to determine whether low-dose or standard-dose CSP in combination with MTX is optimal for Japanese patients who undergo allogeneic BMT from HLA-identical siblings.

Between October 1981 and December 2000, 46 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) underwent allogeneic hematopoietic stem cell transplantation (HSCT) in the Nagoya Blood and Marrow Transplantation Group. The median age was 28.5 years (range, 4-51 years). All but one patient achieved engraftment. Grade II-to-IV acute graft-versus-host disease (GVHD) developed in 32.5% of patients, and chronic GVHD developed in 40.5%. The incidences of relapse and treatment-related mortality (TRM) at 5 years were 65% and 26%, respectively. The estimated overall survival rate at 5 years was 23%. Univariate analysis showed that improved disease-free survival (DFS) was independently associated with complete remission (CR) at transplantation (39%), compared with non-CR (8%) (P = .023). Non-CR at transplantation was associated with a higher risk of relapse. Donor type, acute GVHD, and time from diagnosis to HSCT all had a significant effect on TRM. In a multivariate analysis, 9 months or more from diagnosis to HSCT was the only variable statistically significant for DFS (relative risk, 3.22; P = .01). This study demonstrates that allogeneic HSCT cures a significant population of patients with Ph+ ALL. Relapse is the major obstacle limiting the success of HSCT. Early transplantation during CR from donors, including unrelated persons or mismatched relatives, may offer improved long-term DFS.

The purpose of this study was to assess the efficacy and safety of interferon (IFN) treatment in patients with a relapse of chronic myelogenous leukemia (CML) after bone marrow transplantation in Japan. Accordingly, we retrospectively analyzed the results obtained from 8 patients treated with IFN by the Nagoya Blood and Marrow Transplantation Group. One of 3 patients with hematologic relapse and all 5 patients with cytogenetic relapse achieved complete cytogenetic response (CCR). The median time to achieve CCR was 8 months (range, 3-16 months). One patient relapsed 9 months after starting IFN and died of blast crisis. CCR was maintained for a median duration of 47 months (range, 9-79 months) in the remaining 5 patients. The median duration of survival of these 5 patients after starting IFN was 58 months (range, 12-89 months). At the time of this report, 2 patients who did not attain CCR have survived for 81 months and 142 months after starting IFN, respectively. During IFN treatment, 1 patient showed a transient deterioration of chronic graft-versus-host disease, and no treatment-related deaths were observed. These results suggest that treatment with IFN for CML patients who relapse after bone marrow transplantation is effective and safe. A prospective study to compare IFN with donor lymphocyte infusion is necessary to establish the optimal strategy for the treatment of CML patients who relapse after bone marrow transplantation.

The effect of early treatment of cytomegalovirus (CMV) antigenemia with ganciclovir (DHPG) for the prevention of CMV disease was evaluated in 25 patients with hematological malignancy who had received marrow from human leukocyte antigen-matched unrelated donors at our institution. CMV antigenemia occurred in 17 of 25 patients, a high rate of 68%, and was initially detected between 4 and 8 weeks after bone marrow transplantation (BMT) (median time 5 weeks). The incidence of CMV antigenemia was statistically higher in those patients given steroids or antithymocyte globulin (P < 0.01). All 17 CMV antigenemia-positive patients were treated with DHPG until antigenemia was cleared, and this treatment was resumed if antigenemia occurred. CMV antigenemia eventually became negative in all cases. One major drawback of DHPG was that leukopenia was observed in six patients (35%). CMV disease occurred in six patients despite early treatment of CMV antigenemia with DHPG (24%, 6 of 25 patients). Four of them developed CMV disease in the early phase (within six months) and two in the late phase (more than six months). All CMV diseases in the early phase were easily cured by treatment with DHPG while monitoring CMV antigenemia, but CMV disease in the late phase did not respond to DHPG and led to the death of one patient. On the other hand, there were no patients who developed CMV disease in the antigenemia-negative group. Thus, although early treatment using our method was effective in clearing CMV antigenemia in unrelated BMT, it did not totally prevent CMV disease. A further method of early treatment for the prevention of fatal CMV disease is required.

We studied the immune reconstitution and incidence of chronic graft-vs-host disease (GVHD) and infection in 25 patients who survived more than 1 year after bone marrow transplantation (BMT) from unrelated donors for treatment of leukemia. Of the 25 patients, 4 died after 1 year post-transplantation. The causes of death were relapse of leukemia (2 patients), obstructive bronchiolitis (1 patient), and hepatic failure (1 patient). Only 2 of 14 patients who were under 30 years of age at the time of their BMT developed chronic GVHD, however, 7 of 11 patients 30 years of age or older developed chronic GVHD. Lower karnofsky scores were displayed by 6 of the older patients with chronic GVHD but by none of the younger patients with chronic GVHD. These results underscored the importance of care for older patients with chronic GVHD.CD4-positive T cells, and especially CD4 * CD45RA-positive T cells, had not recovered to a normal range even 2 years after BMT. Longer follow-up will be necessary.

We established a simple method of T cell depletion using anti-CD6 monoclonal antibody-conjugated immunomagnetic beads. Preliminary experiments using this method demonstrated that CD3+ T cells could be partially depleted without depleting CD56+ NK cells. A phase I-II clinical study was performed to assess the safety and efficacy of this partial T cell depletion method for the prevention of acute graft-vs.-host disease (GVHD) in 10 leukemia patients at high risk for GVHD (defined as 1) unrelated transplant from MLC-positive or HLA-DRB1 mismatched donor or 2) related transplant from serologically HLA-A, -B, or -DR one-locus mismatched donor). Cyclosporine (CSP) and methotrexate (MTX) were used for additional prophylaxis against GVHD in all cases. Sustained engraftment occurred in 9 of the 10 patients. Although acute GVHD developed in 6 of the 9 evaluable patients, none developed more than grade III severe acute GVHD. Five patients were alive in remission at a median follow-up of 32 months after bone marrow transplantation, and no relapse of leukemia was observed. We conclude from this pilot study that selective T cell depletion with anti-CD6 monoclonal antibody coupled with CSP and MTX posttransplant immunosuppressive therapy is safe. Further analysis of the phase II-III study is needed to confirm the effectiveness of this protocol.

Fifty leukemia patients were given bone marrow transplants (BMTs) from unrelated donors at Meitetsu Hospital. We studied the outcomes of their transplants from two perspectives: leukemia disease stage and acute graft versus host disease (GVHD). The probability of disease-free survival for standard-risk, high-risk, and super-high risk patients was 65%, 29%, and 8%, respectively. The main causes of death were septicemia, cardiac and renal failure, and relapse of leukemia in the high- and super-high risk patients, and grade III-IV acute GVHD in the standard-risk patients. The incidence of grade II-IV and grade III-IV acute GVHD was 32% and 17%, respectively. All 7 patients in whom grade III-IV severe acute GVHD developed died. We conclude that better control of acute GVHD and treatment of early stage complications are clearly important to improving the outcome of BMTs from unrelated donors, especially for high and super-high risk patients.

The effects of regimens on the prevention of infection in 42 adult leukemia patients receiving bone marrow transplantation was analyzed. Standard risk patients (transplantation in 1st remission of acute leukemia and chronic phase of chronic myelogeneous leukemia received marrow from HLA compatible sibling or autologous marrow) showed shorter febrile days than high risk patients (transplantation in more advanced stage of leukemia and transplantation from unrelated donor), 1.33 mean days vs. 4.93 mean days respectively. Poorer intake of non-absorved antibiotics resulted in higher rate of bacterial colonization in stool after transplantation. And that, the degree of gut sterilization correlated with the duration of febrile days during the period of less than 100/microliter peripheral neutrophil count in high risk patients. Thus, prophylactic regimens of infection in bone marrow transplantation should be considered according to the risk of patient, that is, more practical and complete prophylaxis in risk patients and more conventional one in standard risk patients.

In October, 1989, the Tokai Marrow Donor Bank (TMDB) was established through the cooperation of patients' families, the branches of blood centers of Japanese Red Cross and the hematologists' group in Tokai Area (Aichi, Shizuoka, Gifu and Mie Prefectùres) in Japan to facilitate the procurement of suitable marrow from unrelated volunteer donors for patients lacking related donors. The number of human leukocyte antigen (HLA)-A, B typed donors totaled 3,083 and the number of patients registered for donor search totaled 1,415 by June 1992, when the activities of TMDB were transferred to the newly created Japan Marrow Donor Program (JMDP), and 55 transplanations from unrelated donors facilitated by TMDD were performed.

We present an 18-year-old woman who was diagnosed with acute myeloblastic leukemia (AML M2), and in whom chromosome analysis of bone marrow cells revealed t(7;11), an abnormality rarely found in leukemias with a differentiation potency. She relapsed 1 year after complete remission was achieved by chemotherapy. Bone marrow examination then revealed a t(7;11) abnormality in 48 of 50 metaphases examined, even when there were less than 7.5% leukemic blasts in the marrow, indicating that the morphologically normal cells were derived from leukemic blasts. The number of leukemia clones with the additional abnormalities in chromosome 5 increased, with concurrent development of eosinophilia, fever, asthma-like symptoms, erythema, itching, and hepatosplenomegaly. Elevation of interleukin 5 (IL-5) in serum and an enhanced expression of IL-5 mRNA were also detected. The increase in IL-5 may have been produced by an abnormality on chromosome 5.

The Tokai Bone Marrow Bank was established in 1989 and coordinated 1,415 patients with 3,000 HLA-A, B-typed donors. Of the 1,415 patients, 757 patients had HLA-A, B-identical donors, 206 patients had HLA-DR-identical donors, and 80 patients had MLC-compatible donors. Finally, 55 unrelated donor bone marrow transplantations were done. The most frequent reason of interruption in coordination was disagreement of donor's family. We sent several questions by mail around 1 month after the donation to 55 donors to analyze the psychological reactions of unrelated bone marrow donors to donation. Donors were generally quite positive about the donation. 92% of the donors felt it was worthwhile and no one felt it was not at all worthwhile. 73% of the donors would be willing to donate again in the future. 79% of donors would like to know the clinical course of the patient after the bone marrow transplantation. We hope that these results may be helpful in the development of the Japan Marrow Donor Program.

A novel cDNA clone, A15, was isolated by the differential screening of a cDNA library of an immature T cell line, HPB-ALL using radioactive cDNA probes from the mRNA of either HPB-ALL or peripheral blood lymphocytes. It hybridized to a single mRNA species of about 2.0 kilobases which is expressed in HPB-ALL cell line, but not in the PBL or a promyelocytic leukemia cell line, HL-60. The A15 gene codes for a protein of 244 amino acids which contains four potential transmembrane domains and four possible N-linked glycosylation sites. A computer-aided comparison showed a marked similarity to several other membrane proteins: CD9, CD37, CD53, TAPA-1, Sm23, CO-029, and ME491/CD63.

Forty-one consecutive adult patients with acute myeloid leukemia (AML) were treated with an intensive individualized induction therapy of behenoyl cytarabine, daunorubicin, and 6-mercaptopurine, 29 patients (71%) achieved complete remission (CR). Patients then received three courses of intensive consolidation therapy, including intermediate-dose continuous cytarabine (400 mg/m2, for 5 days) and non-cross resistant drugs such as mitoxantron, etoposide and vincristine. During the course of the consolidation therapy, three patients died of infections and one died of myocardial infarction. Four patients underwent allogeneic bone marrow transplantation. The patients then received six courses of moderately intensive maintenance therapy for 1 year. The predicted 5-year continuing CR and disease-free survival rates of the CR patients were 62% (95% confidence limit, 41% to 83%) and 53% (33% to 73%), respectively. Although the number of patients in this study is small, the present study indicated that it may be possible to cure a fairly large proportion of AML patients by chemotherapy alone, if intensive induction therapy is followed by intensive consolidation therapy.