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A phase II study of mitoxantrone (Novantrone; dihydroxyanthracenedione) was conducted in 35 patients (22 male: 13 female) with acute leukemia. There were 35 evaluable cases with a mean age of 34 (range 8-61). Twenty-eight patients had acute non-lymphocytic leukemia (ANLL) and seven had acute lymphocytic leukemia (ALL). Mitoxantrone was administered intravenously 2-4 mg/m2 daily for five days and after the nadir a further 2-3 doses were added if necessary. All previously treated cases (22 patients) had been treated with anthracyclines; 13 had no previous treatment. Out of the 13 untreated cases there were six complete remissions (CRs) (46.2%) and five partial remissions (PRs) (38.5%), while out of 22 pretreated cases, four CRs (18.2%) and five PRs (22.7%) were obtained. In seven of the untreated cases the decrease of leukemic cells and neutrophil leukocytes were analysed. Mitoxantrone showed a longer duration of decrease and higher log decrease of leukemic cells in the bone marrow than daunorubicin or cytosine arabinoside. Seventy-three percent of patients showed gastrointestinal disturbances such as nausea or loss of appetite. In 38.1% SGPT elevation and in 8.8% abnormal ECG findings were observed. All side-effects were mild and reversible. From this data mitoxantrone seems a very promising agent in the treatment of acute leukemia and a phase III study is now being carried out.

We describe the rearrangement of immunoglobulin genes and T3 expression in the absence of rearrangement of T-cell receptor beta-chain genes in a patient with T-cell malignant lymphoma. He had a mediastinal mass and his lymphoma cells expressed T-cell antigens (OKT3+, OKT9+, and OKT10+). When we examined genomic DNA from the lymphoma cells, we detected the rearrangement of immunoglobulin heavy chain genes with a germ-line configuration of light chain genes and no rearrangement of T-cell receptor beta-chain gene. These results indicated that the rearrangement of immunoglobulin genes could occur in T-cell malignant lymphoma, and that T3 antigen could be expressed prior to the rearrangement of T-cell receptor beta-chain genes under certain circumstances.

An open-label, prospective, multicenter study was conducted between October 2006 and March 2010 to assess the efficacy and safety of intravenous voriconazole (VRCZ) as empirical therapy for antibiotic-refractory febrile neutropenia in Japanese patients with hematological disorders. In addition, to find the patient groups that may benefit from antifungal therapy, the definition of invasive fungal infection proposed by EORTC/MSG (2002) was assessed in this study. Plasma (1-3)-β-d-glucan and Aspergillus PCR in blood were also measured to improve the diagnostic accuracy. A total of 103 patients (median age, 59 years), including 25 undergoing induction chemotherapies and 19 allogeneic hematopoietic cell transplants, were evaluable. Sixty-nine percent of the patients achieved resolution of clinical symptoms and 31% achieved treatment success, defined as fulfilling the previously described five-part composite endpoint. Although VRCZ was discontinued in 9.7% of the patients because of adverse effects, all the patients recovered soon after discontinuation of VRCZ. The treatment success rate of VRCZ appeared to be higher in patients categorized as “not classified” compared with “possible invasive fungal disease” according to the EORTC/MSG criteria. Moreover, six “not classified” patients were positive for either plasma (1-3)-β-d-glucan (n=5) or Aspergillus PCR in blood (n=2). The present study demonstrates that empirical VRCZ therapy is safe and effective in Japanese patients. Additionally, (1-3)-β-d-glucan and Aspergillus PCR tests were expected to provide additional information on the diagnosis of invasive fungal infections.

36歳, 女性の, 慢性骨髄性白血病にて骨髄移植施行後に連続して発症したKeratoacanthomaの1例を報告した。Keratoacanthomaの病因については, 多くの因子の関与が推測されているが, いまだはっきりしておらず, 我々の症例の様に骨髄移植後に免疫抑制剤を使用してきた免疫抑制状態に至って発症した事は免疫抑制状態もKeratoacanthomaの発生の1つの因子になる事が推測された。

Bone-marrow transplantation has been used in patients with acute lymphoblastic leukaemia (ALL) thought to be at high risk of relapse if managed with chemotherapy. Data from 444 ALL patients with one or more high-risk features at diagnosis were analysed to evaluate outcome after HLA-identical bone-marrow transplantation during first or during second remission. The 4-year actuarial probability of leukaemia-free survival was 45% (95% confidence interval 36-54%) for transplants in first remission compared with 22% (15-29%) for those in second remission (p less than 0.0002). The 4-year probabilities of relapse were 26% (14-38%) and 56% (45-67%) respectively (p less than 0.0001). For high-risk ALL, transplantation in first remission had clearly superior results to transplantation in second remission. Further studies are needed to determine whether patients with high-risk ALL should receive transplants during first remission or should initially receive chemotherapy, with transplantation being reserved for patients who relapse.

In order to find the level of leukemic cells during remission a differential count of 5,000 leukocytes was made in 91 acute nonlymphocytic leukemia cases during their first complete remission. Patients were divided into three groups according to the level of leukemic cells, i.e., 0-1/5,000, 2-4/5,000 and 5-/5,000. A close correlation was observed between the survival of patients and the level of leukemic cells and their tendency to decrease or increase during remission. All patients in whom leukemic cells rose from 0-1/5,000 to a level higher than 8/5,000 suffered a documented relapse after 4-8 weeks. This method appears to be a good supportive examination for acute leukemia patients during remission.

A Phase II study of recombinant granulocyte colony-stimulating factor (G-CSF) in allogeneic bone marrow transplantation (BMT) was performed. The recovery of leukocytes and neutrophils was markedly accelerated in G-CSF-administered recipients. The days to WBC count greater than 1,000/microliters (11.5 +/- 1.9) and the days to neutrophil count greater than 500/microliters (11.5 +/- 1.4) were significantly shorter than those of the monocyte-CSF (M-CSF) and CSF(-) groups. In the G-CSF group the WBC count at nadir was higher than in other groups, and neutrophil recovery preceded monocyte recovery. After the discontinuation of G-CSF, the WBC count first decreased for a few days and then increased again slowly. The short duration of leukopenia brought about a reduction in the number of febrile (greater than 38 degrees C) days which, until day 30, were 1.8 +/- 1.9 in the G-CSF group, also significantly shorter than in others. Acute graft-versus-host disease (greater than grade II) appeared in two of eight patients from the G-CSF group, this incidence being comparable to those found in the other groups. A side effect of G-CSF-mild bone pain-was observed in one patient, but it was tolerable. Six of eight patients in the G-CSF group survived for between five and 13 months after BMT with a Karnofsky score greater than 90%. No relapses were observed in the six, including one patient with chronic myelogenous leukemia and two with acute non-lymphoblastic leukemia. To determine the final influence of G-CSF on myeloid leukemia, further long-term follow-up studies are needed. G-CSF was well tolerated and seemed promising against allogeneic BMT.

We assayed the capacity of tumor promoters to induce human T-cell leukemia/lymphoma virus (HTLV) structural proteins p19 and p24 from the HTLV genome-carrying adult T-cell leukemia (ATL) cell lines, MT-1 and KH-2 l o, and fresh ATL cells. Among the tested substances, 12-O-tetradecanoyl phorbol-13-acetate (TPA), 12-hexadecanoyl-phorbol-13-acetate (HPA) and teleocidin induced HTLV structural protein p19 and p24. This suggests that certain environmental substances, especially those known to be tumor promoters, may activate the HTLV-gene in ATL cells.

Data from 547 patients with aplastic anaemia who received bone marrow transplants from HLA-identical siblings were analysed to determine factors associated with the risk of interstitial pneumonia (IPn). IPn developed in 92 patients (17%). 37% of cases were associated with cytomegalovirus infection and 22% with other organisms; in 41% of cases no organism was identified. The case fatality rate was 64%; the mortality rate due to IPn was 11%. In multivariate analysis, four factors were associated with an increased probability of interstitial pneumonia: use of methotrexate rather than cyclosporine after transplantation (relative risk, 2.8; P less than 0.0008); occurrence of moderate to severe acute graft-versus-host disease (relative risk, 2.2; P less than 0.002); inclusion of total body radiation in the pretransplant preparative regimen (relative risk 2.2, P less than 0.004); and patient age greater than 20 (relative risk 1.7, P less than 0.002). The probability of IPn ranged from 4% for patients with none of these adverse risk factors to 51% (relative risk of 13.4) for patients with all four. The incidence of IPn decreased significantly between 1978 and 1985, paralleling a decrease in the use of total body radiation pretransplant for immune suppression and methotrexate post-transplant for prophylaxis against graft-versus-host disease.

The in vivo dose-response potential of recombinant human granulocyte colony-stimulating factor (rG-CSF) in facilitating reconstitution of granulopoiesis was evaluated in an 11-year-old girl who received autotransplantation of peripheral blood stem cells (PBSC) after marrow-ablative therapy for relapsing acute lymphoblastic leukemia. The recovery of hematopoiesis was slow when a small number of progenitors were collected and reinfused into the patient, but administration of rG-CSF led to significant dose-dependent increase in peripheral blood granulocytes.

A new water-soluble nitrosourea derivative, methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), was found to be useful for the treatment of chronic myelogenous leukemia (CML) in the chronic phase. To compare the efficacy of MCNU with that of busulfan, patients were randomized. In the 40 patients administered MCNU, the median time to the achievement of a complete remission (CR) was 50 days. This value was shorter than that observed in 37 patients administered busulfan (126 days, p less than 0.05). There were no differences in the rate of CR achieved, mortality, median time to the onset of blast crisis (BC), BC rate, or survival rate during the observation period. The overall incidence of side effects was higher for MCNU (31%) than for busulfan (15%), but the symptoms were mild, transient and tolerable for most patients. These results suggest that MCNU is a safe and valuable addition to the therapeutic repertoire for the control of CML.

Acute graft-versus-host disease (GvHD) is an important complication of bone marrow transplantation in humans. Risk factors are imprecisely defined and controversial. We analysed data from 2036 recipients of HLA-identical sibling transplants for leukaemia or aplastic anaemia to identify risk factors for GvHD. Analyses indicate that grading of GvHD can be reproducibly divided into absent or mild versus moderate to severe; 2-year actuarial probability was 54% (95% confidence interval 52-56%) for absent or mild and 46% (44-48%) for moderate to severe. Factors predictive of development of moderate to severe GvHD include donor/recipient sex-match (female----male greater than others, relative risk 2.0, P less than 0.001). This risk was markedly increased if female donors for male recipients were previously pregnant or transfused (relative risk 2.9, P less than 0.0001). Older patients were at increased risk of GvHD (relative risk 1.6, P less than 0.001), but the age gradient was modest, even the youngest patients had a substantial risk of GvHD and, if parous or transfused female----male transplants were excluded, age was not a significant risk factor. Cyclosporine or methotrexate were equally effective at preventing GvHD and were superior to no prophylaxis (relative risk 2.3, P less than 0.01). These data should be useful in estimating the risk of acute GvHD in an individual patient and in designing clinical trials to investigate methods to modify or prevent GvHD.

In a cooperative randomized control study of immunotherapy with bestatin in combination with chemotherapy in adults with acute nonlymphocytic leukemia (ANLL), 101 patients (48 in the bestatin group and 53 in the control group) out of 115 patients registered were evaluated as eligible. The bestatin group achieved a statistically significant prolongation of survival compared with the control group in overall ANLL and acute myelogenous leukemia. In the analysis of patient age, the bestatin group achieved a statistically significant prolongation of both the remission duration and survival in patients aged 50 to 65 years, while the differences were not significant in the 15 to 49 age group. The bestatin group tended to achieve a higher rate of reinduction of remission in patients who had recurrence of leukemia. Side effects developed in only 5 (9.6%) of 52 patients treated with bestatin. None of these side effects were particularly serious in nature. It is concluded that bestatin is useful for prolongation of survival of adult patients with ANLL, making for a longer remission duration especially in elderly patients and with few side effects.