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This prospective multicenter study was performed to clarify the efficacy and safety of micafungin (MCFG) as an empirical antifungal therapy for suspected fungal infection in patients with hematological disorders and neutropenia. Three hundred and eighty-eight patients were enrolled; 151 patients with possible fungal infection diagnosed by radiological imaging or serological testing and 237 patients with refractory fever were included in this study. The mean dose and duration of treatment with MCFG were 154.6 mg/day and 14.0 days, respectively. The clinical response rate for patients with possible fungal infection and refractory fever was 60.1% and 65.3%, respectively. Even in persistent neutropenic patients with a neutrophil count of

The study was conducted as a prospective multicenter trial to evaluate the efficacy and safety of micafungin in patients with invasive fungal infections (IFIs) in hematological disorders. A total of 277 patients was registered, and 197 were assessed for clinical efficacy. The mean dosage and duration of micafungin were 170.7 mg/day and 22.0 days, respectively. The efficacy rates were 87.5% (7/8) for patients with candidiasis, 44.7% (17/38) for probable IFIs, 61.9% (39/63) for possible IFIs and 80.7% (71/88) for those who failed to respond to antibacterials. In patients with febrile neutropenia (below 500 microL), despite broad-spectrum antibacterial treatment over 2 days, 86.3% (44/51) of patients had a favourable response to micafungin. The incidence of adverse events related to micafungin was 14.1% (39/277), but most of them were mild and reversible. These data indicate the usefulness of micafungin as a novel therapeutic drug for both empirical and targeted therapy for IFIs.

We examined effects of combination chemotherapy with dexamethasone, melphalan, vincristine, and MCNU (DMVM), plus IFN-α in patients with previously untreated and treated multiple myeloma (MM). In the study, 78 previously untreated and 47 treated MM patients were evaluated. The overall response rate was 76% [27% complete response (CR)] : 85% [37% CR] in previously untreated patients and 62% [11% CR] in previously treated patients. The 50% survival time was 45.3 months for untreated patients and 30.1 months for previously treated patients. This regimen is effective in producing a high CR rate and prolonging survival duration of MM patients.

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-γ 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-γ 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-γ 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-γ. (J Allergy Clin Immunol 2000;106:S45-50.)

Purpose: The antiemetic effect of granisetron injection at a dose of 40 μg/kg used in the treatment of nausea/vomiting induced by multidrug combined cancer chemotherapy excluding cisplatin in patients with tumors of hematopoietic organs was evaluated by comparing a 30-min infusion and a slow intravenous injection given over 30 s. Methods: A two-group random-allocation comparative study was performed with the cooperation of multiple institutions using a central registration system. Results: In the treatment of acute clinical symptoms, appetite was described as “similar to that during good health” by 61.1% of patients (55/93) in the instillation group and by 47.3% (44/93) in the slow injection group, a significant advantage in the infusion group. However, no significant differences in the number of episodes of vomiting, the severity of nausea or clinical efficacy were found. In the final clinical evaluation and assessment of usefulness based on the subjective judgement of physicians throughout the entire therapeutic period, no differences were discernible. No side effects were reported for either method and there was no indication of a sex difference concerning efficacy. However, the efficacy in patients with an anemic tendency was slightly inferior. Conclusions: The maintenance of appetite during the administration of anticancer drugs is very important to maintain patients' daily activities and quality of life. The present results support the usefulness of infusion of granisetron as an administration method during chemotherapy for malignant hemopathy.

We conducted a phase II multicenter study in order to evaluate the efficacy and toxicity of two combination regimens containing KRN8602 (MX2) for drug-resistant acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). AML was treated with KRN8602, 15 mg/m2 i.v. push for 5 days, and cytarabine (AraC), 100 mg/m2 by 24 h coutinuous infusion for 7 days. ALL was treated with KRN8602, 15 mg/m2 i.v. push for 5 days, vincristine (VCR), 1.4 mg/m2 i.v. push, once weekly, and prednisolone (PSL), 40 mg/m2, 3 h infusion for 5 days. In AML and ALL, the complete remission (CR) rate was 36.4% (16 of 44) and 24.1% (seven of 29), and the overall response rate (CR+PR) was 52.3% (23 of 44) and 51.7% (15 of 29), respectively. Among the 29 relapsed cases of AML, a higher CR rate, 51.7% (15 of 29), was obtained. A high incidence of nausea/vomiting and anorexia was observed, and some patients experienced central nervous system disorders and peripheral neuropathy. There was a low incidence of severe neurotoxicities; all other toxicities were manageable. KRN8602 was found to overcome drug resistance clinically, confirming results based on the preclinical studies. We conclude that KRN8602 is an effective novel anthracycline for drug-resistant acute leukemias.

Itraconazole, an oral antifungal agent, was evaluated for the clinical efficacy and safety in patients documented or suspected of systemic fungal infection (SFI) complicated with hematological malignancies. The data was also evaluated according to serological tests and fungal culture. Out of a total of 79 patients, the clinical efficacy of itraconazole was evaluated in 52 patients, comprising 4 patients with proven SFI, 33 with clinical SFI, and 15 with suspected SFI. The overall efficacy was 67.3% (35/52), in which 25.0% in the established SFI group (1/4), 78.8% in the clinical SFI group (26.33), and 53.3% in the suspected SFI (8/15). When assessed according to the severity of SFI, the effectiveness rates were 75.0% in the mild group (15/20), 76.2% in the moderate group (16/21), and 36.4% in the severe group (4/11), resulting in significantly higher rates in the mild and the moderate groups than in the severe group (p = 0.0479). Out of the 10 patients who were switched from the previous antifungals, 7 patients were judged as showing marked or good responses. All of these patients were switched from intravenous fluconazole therapy. With respect to the safety of itraconazole, among 79 patients eligible for safety evaluation, adverse events such as hepatic dysfunction, increase in GOT and/or GPT, nausea and vomiting, and chest pain were observed in 6 patients (7.6%), and itraconazole may have been associated with them. As a conclusion, itraconazole proved to be effective and safe on SFI developed in patients with various hematological malignancies.

We compared the clinical efficacy and safety of an antibiotic regimen based on the order of sequential administration in patients with hematologic disorders. In group A, 2 g of fosfomycin was injected intravenously, followed by an intravenous drip infusion of 1 to 2 g of sulbactam/cefoperazone 1 hour later. In group B, 1 to 2 g of sulbactam/cefoperazone was administered by intravenous drip infusion, followed 1 hour later by intravenous injection of 2 g of fosfomycin. The efficacy rates were 59% (45/76), and 43% (30/69) respectively. Group A showed a significantly higher efficacy rate than did group B (P=0.035, Wilcoxon rank-sum test). Group A also showed a higher efficacy rate than that found in our previously published studies that used single antibiotic administration. The clinical response for bacteremia was excellent and good in 5 patients of 8 patients, and the efficacy rates were 60% for sepsis and 43% for pneumonia. In group B, the clinical response for bacteriemia was excellent and good in 3 of 6 patients, and the efficacy rates were 42% for sepsis and 25% for pneumonia. The incidence of adverse reactions and abnormal laboratory findings in all patients evaluated for safety was 14% (12/85) in group A and 18% (14/76) in group B. Minimal difference was noted between the groups, and no serious cases were observed. These results suggest that fosfomycin administered first, followed by sulbactam/cefoperazone 1 hour later (as in group A) is an effective antibiotic regimen for severe opportunistic infections in patients with hematologic disorders.

Treatment with busulphan and/or hydroxyurea rarely produces remission in patients with chronic myelogenous leukaemia (CML) in chronic phase. HLA-identical sibling transplants almost always produce remission, and only about 20% of patients relapse post-transplant. The increased anti-leukaemic efficacy of transplants results from intensive pretransplant treatment and immune-mediated anti-leukaemia effects. We studied 433 patients surviving > or = 2 years after diagnosis of CML to determine if patients who have relapsed after a transplant in chronic phase have longer survival from diagnosis than comparable subjects receiving chemotherapy. The chemotherapy cohort included 344 adults < 50 years of age treated on consecutive trials of the Italian Cooperative Study Group on CML between 1973 and 1986. The transplant cohort included 89 patients reported to the International Bone Marrow Transplant Registry who relapsed after an HLA-identical sibling bone marrow transplant carried out between 1978 and 1992. Survivals in the two groups were compared using Cox proportional hazards regression to adjust for prognostic variables. Median survival was 65 months in the chemotherapy cohort and 86 months in the transplant cohort. The 7-year probability (95% confidence interval) of survival was 34% (28-39%) in the chemotherapy cohort and 57% (43-70%) in the transplant cohort (P=0003). There was no difference in survival of patients relapsing after T-cell depleted and non-T-cell-depleted transplants. We conclude that patients who relapse after an HLA-identical sibling bone marrow transplant for CML in chronic phase have longer survival from diagnosis than comparable patients receiving chemotherapy. This effect is most likely to be the result of intensive chemotherapy and/or radiation given for pretransplant conditioning.

PURPOSE To determine whether macrophage colony-stimulating factor (M-CSF) reduces the incidence and duration of febrile neutropenia during three courses of intensive consolidation therapy and whether it shortens time to complete consolidation therapy. PATIENTS AND METHODS In 198 adult patients with acute myeloid leukemia (AML) in complete remission (CR), M-CSF (8 x 10(6) U/d) or placebo was administered from 1 day after the end of each consolidation chemotherapy for 14 days. RESULTS The duration and incidence of febrile neutropenia was significantly reduced by 34% (P = .00285) and 17% (P = .02065), respectively, in 88 assessable patients in the M-CSF group compared with those in 94 assessable patients in the placebo group. Patients in the M-CSF group had 565 days and 133 episodes of febrile neutropenia during 7,901 days at risk, while patients in the placebo group had 977 days and 185 episodes during 9,077 days at risk. The median period required to finish the three courses of consolidation therapy was 93 days in the M-CSF group, which was significantly shorter than 110 days in placebo group (P = .0050). In the M-CSF group, the recovery of neutrophils and platelets was significantly faster (P = .0348 and P = 0.0364, respectively), the administration of systemic antimicrobial agents tended to be less (P = .0839), and the frequency of platelet transfusion (P = .0259) and the total volume of transfused platelets (P = .0292) were significantly less. However, there was no significant difference in the disease-free survival. CONCLUSION M-CSF significantly reduced the incidence and duration of febrile neutropenia during the intensive consolidation therapy, and shortened the time to complete consolidation chemotherapy in AML.

We evaluated the risk of development of second primary cancers, with particular reference to subsequent hepatocellular carcinoma (HCC), in 592 patients diagnosed as non-Hodgkin's lymphoma (NHL), at Osaka Medical Center for Cancer and Cardiovascular Diseases. During 1978-1994, 2,163 person-years of observation were accrued, and 27 of the patients developed a second primary cancer, yielding an observed-to-expected ratio (O/E) of 1.53 [95% confidence interval (CI) = 1.01-2.23]. Significant excess risk was noted for primary liver cancer (PLC; O/E = 4.36, 95% CI = 1.99-8.28; O = 9) and non-lymphocytic leukemia (O/E = 26.17, 95% CI = 5.26-76.46; O = 3). The excess risk of PLC was relatively constant within the first 10 years after the NHL diagnosis. Patients who received chemotherapy as the NHL treatment had a significantly increased risk of PLC (O/E = 5.91, 95% CI = 2.70-11.23; O = 9). Their clinical reports indicated that all nine patients with PLC were diagnosed as HCC, and eight of them had clinical and/or histologic evidence of cirrhosis at the time of HCC diagnosis. None of the nine patients had a history of blood transfusion between the first NHL treatment and the diagnosis of HCC. These findings suggested that Japanese NHL patients might have an increased risk of developing HCC, and they indicated the importance of medical surveillance for liver malignancies, as well as subsequent leukemias. Possible explanations for the excess risk of subsequent HCC are discussed.

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.

A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.

癌化学療法の種々の分野にG-CSFが使用されている。骨髄性白血病細胞の中には, G-CSF受容体をもつものがあり, これに対する注意が必要である。血液疾患合併感染症で抗生剤3日間無効の症例を4日目に randomize してG-CSF(+)と(-)で抗生剤治療を行い有効率に有意差が得られた。顆粒球減少時の感染症に対するG-CSFの効果が証明できたと考えている。骨髄移植では二重盲検試験でG-CSF投与群で顆粒球減少期間の有意の短縮がみられたが, これら症例を5年間追跡するとG-CSF群で慢性のGVHD (Graft versus Host Disease) が有意に低率であることが判った。この成績は説明困難であるので, その再現性につき, アジア太平洋骨髄移植グループでの国際共同研究で, 対照比較試験を行って検討中である。

The WT1 gene encoding a zinc finger polypeptide is a tumor suppressor gene that plays a key role in the carcinogenesis of Wilms' tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine relative levels of WT1 gene expression (defined in K562 cells as 1.00) in 45 patients with acute myelogenous leukemia (AML), 22 with acute lymphocytic leukemia (ALL), 6 with acute mixed lineage leukemia (AMLL), 23 with chronic myelogenous leukemia (CML), and 24 with non- Hodgkin's lymphoma. Significant levels of WT1 gene were expressed in all leukemia patients and for CML the levels increased as the clinical phase progressed. In striking contrast with acute leukemia, the levels of WT1 gene expression for NHL were significantly lower or even undetectable. Clear correlation was observed between the relative levels of WT1 gene expression (< 0.6 v > or = 0.6) and the prognosis for acute leukemia (AML, ALL, and AMLL). Patients with less than 0.6 levels had significantly higher rates of complete remission (CR), disease-free survival, and overall survival than those with > or = 0.6 levels, whereas CR could not be induced in any of the 7 patients with acute leukemia having greater than 1.0 levels of WT1 gene expression. The quantitation of the WT1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence or absence of tumor-specific DNA markers. Continuous monitoring of the WT1 mRNA was performed for 9 patients with acute leukemia. In 4 patients, MRD was detected 2 to 8 months before clinical relapse became apparent. In 2 other patients, the WT1 mRNA gradually increased after discontinuation of chemotherapy. No MRD was detected in the remaining 3 patients with AML who received intensive induction and consolidation therapy. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in 3 patients (2 AML-M3 with PML/RAR alpha, and 1 AML-M2 with AML1/ETO) among these 9 patients detected MRD comparable with that obtained from quantitation of WT1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT1 or promyelocytic leukemia/retinoic acid receptor-alpha gene primers were 10(-3) to 10(- 4) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blood, respectively. Therefore, we conclude that WT1 is a new prognostic factor and a new marker for the detection of MRD in acute leukemia.

Expression patterns of interleukin-6 (IL-6), IL-6 receptor (IL-6R), and gp130 genes in 39 patients with acute myeloid leukemia (AML), in 23 patients with acute lymphoblastic leukemia (ALL), and in 7 patients with acute mixed lineage leukemia (AMLL) were studied by quantitative reverse transcriptase-polymerase chain reaction. Significant levels of IL-6 were expressed in 8 (21%) of 39 AML patients and in 2 (29%) of 7 AMLL patients, whereas in ALL, the expression of IL-6 was almost negligible. IL-6R was expressed in all patients with AML and AMLL, whereas only half of ALL patients expressed low levels of IL-6R as compared with those with AML and AMLL. However, gp130 was ubiquitously expressed in all the leukemia patients, and there was no significant difference in gp130 expression among AML, ALL, and AMLL. Significant correlation was observed between the expression of IL-6R and gp130 in AML. When tested for in vitro response to IL-6, the leukemic cells from 3 of 7 AML, none of 3 ALL, and both of 2 AMLL patients significantly responded to IL-6, showing the correlation between the expression levels of IL-6R and gp130 and the responsiveness of leukemic cells to IL-6. These results showed that quantitation of IL-6R and gp130 expression by reverse transcriptase-polymerase chain reaction is useful for the rapid prediction of the responsiveness of leukemic cells to IL- 6, especially in cases of administration of IL-6.

Expression patterns of interleukin-6 (IL-6), IL-6 receptor (IL-6R), and gp130 genes in 39 patients with acute myeloid leukemia (AML), in 23 patients with acute lymphoblastic leukemia (ALL), and in 7 patients with acute mixed lineage leukemia (AMLL) were studied by quantitative reverse transcriptase-polymerase chain reaction. Significant levels of IL-6 were expressed in 8 (21%) of 39 AML patients and in 2 (29%) of 7 AMLL patients, whereas in ALL, the expression of IL-6 was almost negligible. IL-6R was expressed in all patients with AML and AMLL, whereas only half of ALL patients expressed low levels of IL-6R as compared with those with AML and AMLL. However, gp130 was ubiquitously expressed in all the leukemia patients, and there was no significant difference in gp130 expression among AML, ALL, and AMLL. Significant correlation was observed between the expression of IL-6R and gp130 in AML. When tested for in vitro response to IL-6, the leukemic cells from 3 of 7 AML, none of 3 ALL, and both of 2 AMLL patients significantly responded to IL-6, showing the correlation between the expression levels of IL-6R and gp130 and the responsiveness of leukemic cells to IL-6. These results showed that quantitation of IL-6R and gp130 expression by reverse transcriptase-polymerase chain reaction is useful for the rapid prediction of the responsiveness of leukemic cells to IL- 6, especially in cases of administration of IL-6.

The aim of this study was to evaluate the usefulness of carbapenems as initial treatment for febrile neutropenia (FN), and in patients unresponsive to this initial therapy, to evaluate the efficacy of subsequent treatment with aminoglycosides (AGs) or ciprofloxacin (CPFX). FN patients were randomized to receive cefepime (CFPM, control), panipenem/betamiprom (PAPM/BP), or meropenem (MEPM). Defervescence, an outcome endpoint, was evaluated 3 days later. Patients with minimal response were given CPFX or AGs, and their responses were reevaluated on day 7. A total of 255 patients were included. The efficacies of CFPM, PAPM/BP, and MEPM were comparable. In patients unresponsive to this initial therapy, the efficacy of subsequent CPFX and AGs treatments was also similar. There was no significant between-arm difference in cumulative efficacy on days 14 and 30. Adverse reactions were infrequent and mild. In conclusion, PAPM/BP and MEPM are as useful as CFPM as initial therapy for FN, and AGs are as efficacious as CPFX in patients unresponsive to the initial therapy.

We analyzed the outcome of 450 HLA-identical sibling bone marrow transplants for chronic myelogenous leukemia (CML) in chronic phase performed between 1985 and 1990 and reported to the International Bone Marrow Transplant Registry (IBMTR). All patients received either hydroxyurea (n = 292) or busulfan (n = 158) to treat their CML before transplant. The median interval between diagnosis and transplant was 10 months (range, 1 to 191). Patients treated with hydroxyurea had a higher probability (95% confidence interval) of leukemia-free survival (LFS) at 3 years than those treated with busulfan (61% [51% to 70%] v 45% [36% to 55%], P < .0003). Probability of LFS was also higher in patients transplanted within 1 year of diagnosis (61% [53 to 68%] v 47% [38% to 57%], P < .001). After adjustment for patient and transplant covariables in a multivariate analysis, prior chemotherapy and duration of disease pretransplant were independently associated with LFS. These data support the use of hydroxyurea rather than busulfan and transplant within 1 year of diagnosis for patients with CML and an HLA-identical sibling.

Background. It was assessed whether addition of vincristine (VCR) to remission induction therapy would increase the complete remission (CR) rate, and, secondarily, whether 12 courses of maintenance—intensification therapy would produce longer survival than 4 courses in adult acute myeloid leukemia (AML). Methods. A randomized comparison of individualized induction therapy was conducted between daunorubicin, behenoyl cytarabine, 6-mercaptopurine, and prednisolone with or without VCR. After 3 courses of intensive consolidation therapy, maintenance—intensification therapy was randomized to 4 or 12 courses given every 6 weeks. Results. Of 265 patients registered, 252 were evaluable. CR was obtained in 78%; 80% in 205 patients of age younger than 60 years, and 65% in 47 of age 60 years or older. Addition of VCR reduced the CR rate significantly (84% to 70%, P = 0.007). Predicted 4-year survival, continuing CR, and disease-free survival (DFS) rates of 196 CR patients are 45%, 41%, and 35%, respectively. Patients receiving 12 courses of maintenance—intensification showed better DFS. By multivariate analyses, significant factors for achievement of CR were performance status 0 to 2, age younger than 60 years, and no VCR; and those for longer DFS were achievement of CR by one course, age younger than 50 years, and French—American—British (FAB) classification M3 or M5. Among 131 patients randomized to the maintenance, the administration of 12 courses was the most important factor (P = 0.0040) for longer DFS, followed by FAB M3 or M5, and by achievement of CR by one course. Conclusions. Addition of VCR in remission induction therapy was harmful, and longer intensive maintenance therapy prolonged DFS in adult AML.

Background. MST-16, a new orally administered bis(2,6-dioxopiperazine) analogue and an inhibitor of topoisomerase II, was given to 24 patients with adult T-cell leukemia-lymphoma (ATLL) in a Phase I-II multiinstitutional cooperative study. Methods. MST-16 was administered orally daily for 7 days, with courses repeated at intervals of 2–3 weeks in 24 patients. Results. Two complete remissions (CR) and eight partial remissions (PR) were obtained in 23 evaluable patients who received 1200–2800 mg/day of MST-16. Among 13 acute-type ATLL, one CR and five PR were obtained. Among eight lymphoma-type ATLL, two PR were detected. Among two chronic-type ATLL, one CR and one PR occurred. Remissions were obtained at 7–232 days (median, 23 days) and lasted 43–374 days (median, 68 days). The major toxic effects were leukopenia (68%), anemia (52%), thrombocytopenia (35%), and gastrointestinal disorders (22%). Conclusions. MST-16 was shown to be effective in ATLL, which has no standard therapy. This drug deserves further clinical trials because it shows little cross resistance to currently available antitumor drugs.

Optimal prophylaxis of graft-versus-host disease (GVHD) is controversial. We compared efficacy of three posttransplant immune suppressive regimens in 2,286 recipients of HLA-identical sibling bone marrow transplants for acute lymphoblastic leukemia (ALL) in first remission, acute myelogenous leukemia (AML) in first remission, or chronic myelogenous leukemia (CML) in first chronic phase. Six hundred forty received methotrexate, 977 received cyclosporine, and 669 received combined cyclosporine and methotrexate. In children, the three regimens resulted in similar outcomes. In adults, cyclosporine and methotrexate had comparable risks of acute and chronic GVHD. Compared with methotrexate, cyclosporine was associated with less interstitial pneumonia (relative risk [RR] = 0.6; P < .001), less treatment-related mortality (RR = 0.6; P < .001), more relapses (RR = 1.6; P < .05), and less treatment failure (relapse or death from any cause; RR = 0.7; P < .001). Different effects were observed in different leukemias. In ALL, the rate of leukemia relapse was increased with cyclosporine versus methotrexate, with no effect on other outcomes. In AML and CML, interstitial pneumonia, treatment-related mortality, and treatment failures were decreased with cyclosporine, with no increase in relapse. Similar analyses comparing cyclosporine plus methotrexate with cyclosporine alone showed that adults receiving the combination had less acute GVHD (RR = 0.5; P < .001), less chronic GVHD (RR = 0.7; P < .01), and less interstitial pneumonia (RR = 0.7; P < .001). Treatment failure (RR = 0.8; P < .05) was marginally reduced. Separate analyses in ALL and AML showed less acute GVHD with combined therapy, but no significant effect on other outcomes. In CML, acute GVHD, interstitial pneumonia, treatment-related mortality, and treatment failure were decreased with combined therapy.

l-P-Z)-Arabinofuranosylcytosine-5’-stearylphosphate (fosteabine) was administered orally to patients with myelodysplastic syndromes (MDS); refractory anemia with excess of blasts (RAEB), RAEB in trans

This study showed several accumulated data through ten years from our experience in hematopoietic disorders and associated infections, which has been analyzed by the Hanshin Study Group of Hematopoietic Disorders and Infections. Since 1979 to 1988, our group had evaluated the sorts of causative organisms and the efficacy of various antibiotics therapy in 2119 cases of infectious diseases associated with hematopoietic disorders. On behalf of evaluating the changes of disease profile for ten years, we divided the accumulated data into three phases; former phase the first three years, middle phase the second three years and late phase the last four years. There was no significant difference in the frequency of various hematopoietic disorders among the three phases. Each leukemia patients occupied 77% of all cases. Sepsis suspected is the most frequent infectious disease accounting for 68.8%. The other infectious diseases were 8.4% of the sepsis, 14.8% of the respiratory infections and 3.1% of the urinary tract infections. Comparing the frequency of infections among the three phases, the respiratory and urinary tract infections inclined to decrease. Of the 532 strains isolated from 2119 cases and identified as causative organisms, gram-negative bacilli occupied 62.8% and gram-positive bacteria 36.5%. In comparing the percentage of gram-negative bacilli among the three phases, it showed a decreasing tendency in order former phase 63.6%, middle phase 76.4% and late phase 43.8%. Pseudomonas, however, had been isolated at almost constant ratio through ten years. On the other hand, the ratio of gram-positive bacteria isolated were 34.5% in former phase, 23.6% in middle phase and 56.3% in late phase, showing increasing a tendency through the period. Twenty-three kinds of antibiotics were administered by intravenous drip infusion. The efficacy rate was 43.9% to 67.2%. In particular, effectiveness of antibiotic therapy often depends on the change of peripheral neutrophil counts from the onset and during the therapy. The efficacy rate, however, was 36% even neutrophil counts have not shown the tendency of increase from less than 100/microliters.

The cost of treating neutropenic patients unexplained fever is of significant concern in Japan because of the depressed economy and the aging population. Development of a standardized treatment methodology specifically tailored to the situation in Japan will make the treatment more efficient for health care institutions, will allow for improved monitoring of practices and costs, and will result in better patient care. It is essential, however, that the welfare of the patients be the utmost priority--cost savings is not sufficient in the absence of a significant impact on morbidity and mortality.

A multicenter open randomized trial was conducted to compare cefepime monotherapy with cefepime/amikacin combination (dual) therapy in treating febrile neutropenic patients with hematologic disorders. Among the 189 evaluable patients, 5.8% had microbiologically and 10.6% had clinically documented infections. Excellent response was seen in 32.6% and 45.7% of monotherapy and dual therapy recipients, respectively, at day 3 (P=.065). At day 3, patients with neutrophil counts of

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. (J Allergy Clin Immunol 1999;103:S457-61.)

To determine the potential of Tc-99m MIBI for detecting bone marrow malignancy, MIBI imaging of the femur was evaluated. There was no detectable MIBI activity in 125 of 141 (89%) control patients. Clearly demonstrated focal or tubular MIBI activity indicating intramedullary accumulation was demonstrated in 44 of 45 (98%) patients with proven marrow malignancy: 9 patients with multiple myeloma, 10 patients with malignant lymphoma, 11 patients with acute leukemia, 1 patient with chronic leukemia, and 14 patients with skeletal metastases. No abnormal MIBI activity was observed in the femur in 19 of 22 (86%) patients who had no evidence of malignant involvement in the femoral marrow, in 3 patients with solitary plasmacytomas of the spine, sternum or iliac bone, or in 16 patients with malignant lymphoma. In 12 of 24 patients with acute leukemia in complete remission, no abnormal MIBI accumulation was shown in the femur, but in 12 patients, abnormal accumulation indicating residual leukemic activity was demonstrated. MIBI imaging correlated extremely well with MRI studies ; 26 of 28 patients with focal or tubular increased MIBI activity in the femur showed decreased signal on T1-weighted images and a high signal on short inversion recovery images, and 1 patients with no abnormal activity showed a high signal on T1 images. MIBI imaging of the femoral bone marrow may be a new modality for detecting marrow malignancy.

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. (J Allergy Clin Immunol 1997;100:S70-72.)

PURPOSE To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.

Thirty-one patients (27 with acute myeloid leukemia [AML], 2 with acute lymphocytic leukemia [ALL], and 2 with acute mixed lineage leukemia [AMLL]) treated with conventional chemotherapy (CHT) and 23 patients (13 AML, 5 ALL, and 5 with chronic myeloid leukemia [CML]) treated with allogeneic bone marrow transplantation (BMT) were monitored for WT1 expression levels in BM and peripheral blood (PB) by reverse transcriptase-polymerase chain reaction over a long-term period (mean, 29 months for CHT and 24 months for BMT). Sixteen of the patients in the CHT group and 3 in the BMT group who had achieved complete remission suffered clinical relapse. In 10 of these patients, WT1 expression that had returned to normal BM levels (< 10(-3); the WT1 expression level of K562 cells was defined as 1.0) after complete remission (CR) either gradually or rapidly increased again to abnormal levels 1 to 18 months (mean, 7 months) before clinical relapse became apparent. In another 9 patients, WT1 expression never returned to normal BM levels even after CR and the subsequent relapse was accompanied by a rapid increase in WT1 expression to levels higher than 10(-2) (10(-3) levels in PB). On the other hand, the remaining 35 patients (15 CHT and 20 BMT) maintained their CR. In 29 of these patients (11 CHT and 18 BMT), WT1 expression either gradually or rapidly decreased to normal BM levels, whereas in the other 6 (4 CHT and 2 BMT), low or very low levels of WT1 mRNAs (10(-3) to 10(-2) in BM and 10(-5) to 10(-3) in PB) remain detectable, but without any clinical signs of relapse. A clear correlation was found to exist between the minimal residual disease (MRD) detected in the paired BM and PB samples for all types of leukemias (AML, ALL, and CML), with MRD in PB being approximately one-tenth of that in BM. WT1 quantitation of 168 paired BM and PB samples showed that PB samples were superior to BM samples for the detection of MRD. We conclude that monitoring of WT1 expression levels in BM and PB makes it possible to rapidly assess the effectiveness of individual treatment and diagnose clinical relapse in the early stage for all leukemia patients regardless of the presence or absence of tumor-specific DNA markers.

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%.

Abstract 1037 Background: In the IDSA guideline published in 2010 on the use of antimicrobial agents in neutropenic cancer patients, monotherapy with an anti-pseudomonal beta-lactam agent, such as cefepime (CFPM), carbapenem [meropenem (MEPM) or imipenem-cilastatin (IPM)], or piperacillin-tazobactam, is recommended as an empiric therapy for high risk febrile neutropenia (FN) patients. There have been few reports on the efficacy of cefozopran (CZOP), one of the 4thgeneration beta-lactams, in the treatment of such patients. We conducted an open-label randomized controlled study to evaluate the clinical efficacy of CZOP, MEPM, or IPM in high-risk FN adult patients with hematologic malignancies and solid tumors, using CFPM as a control. Methods: In this trial, 386 patients registered from 23 centers were randomized to receive either 4thgeneration beta-lactam (CFPM 2g, q12h IV or CZOP 2g, q12h IV) or carbapenem (MEPM 1g, q12h IV or IPM 1g, q12h IV). The primary endpoint was response to treatment defined as complete defervescence by day 7 with improvement in infection-related symptoms and laboratory findings. The clinical data were analyzed both by intention to treat and per protocol. We also evaluated the efficacy of each of the initial four drugs at days 3 to 5as a secondary endpoint. Results: 386 patients received the assigned antibiotic (CFPM: n=95, CZOP: n=98, MEPM: n=96, IPM: n=97) and 377 were evaluated for efficacy (CFPM: n=94, CZOP: n=95, MEPM: n=94, IPM: n=94). The 4 groups were comparable in terms of the baseline characteristics, including as age (median: 59 years (range: 17–87)), sex (male: n=215, female: n=171), body weight (median: 55 kg (range: 32–100)), underlying malignancy (leukemia: n=212 (54.9%), lymphoma: n=122 (31.6%), multiple myeloma: n=37 (9.6%), myelodysplastic syndrome: n=6 (1.6%), and other malignancy: n=9 (2.3%)), duration of initial antibiotic therapy (median: 7 days (range: 1–29)), median duration of severe neutropenia (neutrophil count < 100×106/L) (median: 6 days (range: 0–56)) and MASCC score (median: 21 (range:3–26)). Only neutrophil count at onset of IPM was significantly lower compared to the other treatments (CFPM: 38×106/L, CZOP: 35 x106/L, MEPM: 18×106/L, and IPM: 3×106/L, p=0.003). In intention-to-treat analysis, the response rates at day 7 were not significantly different among the four arms (CFPM: 63%, CZOP: 59%, MEPM: 61%, IPM: 69% (P=0.52)). The three antibiotics investigated in this trial were as effective as the reference agent, CFPM, in both the intention-to-treat and per-protocol populations. In both the intention-to-treat and per protocol analyses, success rates of the initial therapy at days 3 to 5 were not significantly different among four drugs [CFPM: 52 and 54%, CZOP: 46 and 47%, MEPM: 54 and 55%, IPM: 49 and 53% (P=0.70 and 0.68, respectively)]. Conclusions: CZOP, MEPM, and IPM were as effective as CFPM for adult FN patients with hematological malignancies and solid tumors as an empiric therapy. Disclosures: Tamura: Kyowa Hakko Kirin Co., Ltd,: Consultancy.

In a randomized double-blind placebo-controlled phase III clinical trial, the effects of a non-glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (CSF 39-300) were investigated in patients who had received allogeneic bone marrow transplantation. CSF 39-300 was administered at a daily dose of 10 micrograms/kg (maximum dose, 300 micrograms/body) via three-hour intravenous infusions from days 1 to 21 following reinfusion of the marrow. Twenty-eight patients received CSF 39-300 and 25, placebo. The median number of days to recovery for leucocytes (> or = 1000/mm3), neutrophils (> or = 500/mm3), lymphocytes (> or = 300/mm3) and reticulocytes (> or = 20/1000) were significantly shortened (16 vs 20, 17 vs 21 and 22 vs 28, respectively) with CSF 39-300. The duration of stay in laminar-air-flow room after transplantation was also significantly shortened in the CSF 39-300 group (21 vs 30 days). There was no significant difference in the incidence of acute or chronic graft-versus-host disease between the two groups. A follow-up during the year after transplantation revealed there to be no significant difference in either survival rate or leukemia relapse rate between the two groups. CSF 39-300 is therefore considered useful after allogeneic bone marrow transplantation, especially in the early period.

The present multicenter study was undertaken to confirm whether filgrastim/recombinant human granulocyte colony stimulating factor (rhG-CSF) could mobilize residual multipotential stem cells by its G0-shortening effect in patients with aplastic anemia (AA) and induce a multilineage response. Twenty-seven patients with acquired severe or moderate AA received long-term administration (2 to 12+ months) of rhG-CSF in doses from 100 to 400 micrograms/body/day by s.c. injection or 250 to 1,500 micrograms/body/day by i.v. infusion. Twenty-six out of the 27 evaluable patients showed a substantial increase in neutrophils associated with a recovery of myeloid precursors in bone marrow within one month of therapy. Interestingly, 10 out of the 27 patients showed a dramatic improvement in severe anemia after two to ten months of therapy. Moreover, severe thrombocytopenia improved after two to four months of therapy in three out of these ten patients accompanied by a significant increase in megakaryocytes in bone marrow. Clonal cultures of bone marrow cells revealed a recovery in myeloid as well as erythroid precursors in most of these ten patients. In two patients who showed a trilineage response, mixed and megakaryocyte colony formations also recovered. These results suggest that long-term administration of rhG-CSF mobilizes myeloid, erythroid, megakaryocyte and multipotential progenitor cells and induces a multilineage response in some patients with AA.

Clinical experiences with recombinant granulocyte colony-stimulating factor (rhG-CSF) in 13 acute (AML) and four chronic (CML) myelogenous leukemia patients are reported. Sixteen patients received rhG-CSF in support of treatment for life threatening infections and one CML patient in support of induction chemotherapy. After their first induction chemotherapy, six out of eight AML patients showed a rapid increase of neutrophils, recovered from infections and achieved complete remission (CR). One patient, in whom both neutrophils and blasts had increased during rhG-CSF administration, achieved CR through the next administration of chemotherapy (CR rate 87.5%). The last of the eight AML patients showed no increase of neutrophils, and died of interstitial pneumonitis. Two of five AML patients who received rhG-CSF after reinduction chemotherapy for relapsed or refractory leukemia achieved CR, a rate of 40%. In one of the two, the administration of rhG-CSF prior to induction chemotherapy seemed advantageous in achieving CR. During rhG-CSF administration, an increase of blastic cells in peripheral blood was observed in four out of all 13 AML patients. One of three CML patients, with a lymphoid crisis, showed an increase only of neutrophils, and recovered from infection. The other two showed increases of both neutrophils and blasts. One patient with CML in blastic crisis, undergoing induction chemotherapy with rhG-CSF administration, returned to the chronic phase. These clinical experiences suggest rhG-CSF to be effective in supporting infection therapy and in possibly enhancing the sensitivity of myelogenous leukemic blasts to antileukemic agents.

Background: Invasive fungal infections (IFIs) are of serious concern in the management of immunocompromised patients (pts) with hematological disorders. Empiric antifungal therapy is recommended for neutropenic pts with persistent fever, because treatment after confirmation of fungal infection often produces poor outcomes. Micafungin (MCFG), one of the echinocandin families, was launched first in Japan in 2002, and has now been approved in more than 11 countries and areas including the USA and the EU. Although the efficacy and safety of MCFG against both Candida and Aspergillus infections has been shown in many clinical trials, there are few clinical study reports on the empiric therapy of a suspected fungal infection. Here, we report the multi-center study results of MCFG for the empiric antifungal therapy, which were conducted from April 2005 to September 2006 in Japan. Objective: This prospective study was performed to clarify the efficacy and safety of MCFG for the empirical antifungal therapy on suspected fungal infection in pts with hematological disorders and neutropenia. Methods: Study design: A multiple-center, open, uncontrolled study. The investigator registered pts with neutropenia (< 1,000/μl) who met the following criteria to the Subject Registration Center. Suspected fungal infections were divided into two categories: possible fungal infection defined by positive clinical symptoms/findings and serological testing (beta-D-glucan or galactomannan) or diagnostic imaging (chest X-ray or CT scan), refractory fever defined by unexplained persistent fever (an axillary temperature higher than 37.5 °C) after the antibacterial treatment over 2 days and by positive clinical symptoms/findings. IFIs categorized as proven or probable were not included in this study. Efficacy evaluation was performed using an algorithm based on each of the evaluation of clinical symptoms/findings, imaging study findings, and serological tests. Results: 388 pts (M:234, F:154, mean age:57.8 years old) were registered. The mean dosage and duration of treatment with MCFG were 154.6±55.3 mg/day and 14.0±6.9 days, respectively. The main underlying hematological disorders were acute leukemia (61.3%), non-Hodgkin’s lymphoma (18.3%) and myelodysplastic syndrome (10.8%). The number of pts with hematopoietic stem cell transplantation (HSCT) was 76 (19.6%). The clinical response rate (CRR), excluding 4 non-evaluable pts was 63.3% (243/384): 60.1% (89/148) for pts with possible fungal infection and 65.3% (154/236) for pts with refractory fever, respectively. Even in persistent neutropenic pts whose neutrophil counts were < 500/μL throughout the treatment with MCFG, the CRR was high enough: 46.9% (61/130). No difference was observed in the CRR among the main underlying hematological disorders. The CRR in pts with HSCT and other conditions were 63.2% (48/76) and 63.3% (195/308), respectively. Drug-related adverse events (DAEs) were observed in 16.8% (65/388). Serious DAEs such as elevation of serum bilirubin and renal dysfunction was observed in 0.52% (2/388). Conclusion: MCFG was confirmed to have high clinical efficacy and be safe for the treatment of suspected fungal infection in pts with hematological disorders and neutropenia.

Summary A randomized, double-blind placebo-controlled phase III clinical trial was performed to study the effects of human urinary macrophage colony-stimulating factor (hM-CSF) after allogeneic and syngeneic bone marrow transplantation (BMT) in 60 hM-CSP treated and 59 placebo control patients. HM-CSF was administered at a daily dose of 2 ± 105 units/kg from day 1 to day 14 after RMT. Significant differences between hM-CSF and control patients were found in the recovery time to greater than 0. 5 ± 109 granulocytes/1 and the survival rate during the initial 120 d without retransplantation. There was no difference in the incidence or grade of graft-versus-host disease (GVHD). There was no difference in the rate of leukaemic relapse at 24–36 months after BMT in patients with acute lymphocytic. acute non-lymphocytic, or monocytic leukaemia. The results of this trial show that human M-CSF improves the outcome of BMT without any influence on the occurrence of leukaemic relapse or GVHD.

Background. Although colony-stimulating factors have been shown to accelerate recovery from severe neutropenia after intensive chemotherapy or bone marrow transplantation, their use in acute leukemia has been controversial because in vitro they stimulate leukemic colonies as well as normal granulocyte colonies. Methods. We conducted a prospective, randomized, controlled study to determine the safety and efficacy of recombinant human granulocyte colony-stimulating factor (CSF) after a standard course of intensive therapy in 108 patients with relapsed or refractory acute leukemia (67 with acute myelogenous leukemia, 30 with acute lymphocytic leukemia, 9 in blast crisis from chronic myelogenous leukemia, and 2 with acute leukemia arising from myelodysplastic syndromes). Treatment with granulocyte CSF (200 micrograms per square meter of body-surface area per day in a 30-minute infusion) was begun two days after the end of the chemotherapy and continued until the neutrophil count rose above 1500 per cubic millimeter. Results. Treatment with granulocyte CSF accelerated the recovery of neutrophils significantly (P less than 0.01), shortening it by about a week, but it had no effect on platelet recovery. Although the incidence of febrile episodes was almost the same, documented infections were significantly less frequent in the group treated with granulocyte CSF (P = 0.028). There was no evidence that granulocyte CSF accelerated the regrowth of leukemic cells. Fifty percent of 48 patients in the CSF group who could be evaluated and 36 percent of 50 controls had complete remission. The rate of relapse was almost the same in the two groups. Conclusions. It appears that recombinant human granulocyte CSF is safe in acute leukemia, accelerating neutrophil recovery and thereby reducing the incidence of documented infection without affecting the regrowth of leukemic cells. It should be used with caution, however, pending further confirmation of these early results.

Background and Purpose: Severe infections in patients (pts) with hematological disorders (HD) are mostly the result of a compromised immune system by the underlying disease itself including neutropenia aggravated by chemotherapy and conditioning treatment for hematopoietic stem cell transplantation (HSCT). Systemic fungal infections (SFIs) particularly are often encountered in this field associated with morbidity and mortality. It is deemed crucial to initiate an early introduction of antifungal therapy by using criteria for an early diagnosis. Micafungin (MCFG) that was launched in Japan in 2002 and approved in another 3 countries is shown to be safe and efficacious for SFIs. Since there are few clinical reports on the effects of MCFG in a large number of patients, a multicenter study (87 institutions) was initiated to see its efficacy and safety. Methods: The study was conducted from Apr. 03 to Mar. 05 on pts diagnosed with HD, who met any of the following criteria: ptswho are found to have a causative fungus identified by mycological or pathological testing (proven),with a SFI defined by clinical symptoms/findings and serological testing or diagnostic imaging (probable/possible), orwith a suspected SFI identified by unexplained persistent fever (an axillary temperature higher than 37.5 °C) and clinical symptoms/findings (refractory to antibacterial treatment). Efficacy was evaluated by the degree of improvement in clinical symptoms/findings, mycological findings, imaging study findings such as chest X-ray or CT, and fungal serological tests. The overall effects were rated as either “effective” or “ineffective”, based on an algorithm combining these indices. Results: A total of 277 pts were registered to the central office and 276 were evaluable for safety assessment. Eighty-one pts were not evaluable for efficacy due to a violation of entry criteria, etc. Thus 196 pts were assessed for clinical efficacy by the steering committee (118 males and 78 females, the mean age: 56.8). There were 62 pts with HSCT and 134 with chemotherapy in whom 67 had acute leukemia. The mean dosage and duration of MCFG were 170.8mg per day and 21.8days, respectively. Overall clinical effects were achieved in 134 out of 196 pts (68.4%). Clinical response was seen in 72.6% (45/62) for those with HSCT and 66.4% (89/134) for those of chemotherapy and particularly 68.7% (46/67) of the pts with chemotherapy for acute leukemia, respectively. The success rates were 87.5% (7/8) for pts with proven SFIs like candidemia, 44.7% (17/38) for probable SFIs, 62.9% (39/62) for possible SFIs, and 80.7% (71/88) for those who failed to respond to antibacterial treatment. The success rate for 13 pts with persistent fever on antibacterials and neutrophil counts below 500/μL before and after MCFG treatment was 69.2%. The incidence of adverse events related to MCFG was 30.1% (83/276), and the most common one was elevation of liver transaminase levels. Conclusions: MCFG demonstrated excellent clinical efficacy and safety when used to treat possible to proven SFIs in pts with HD, indicating its usefulness as a novel therapeutic drug for both empirical and targeted therapy for deep-seeded fungal infection.

A feasibility study was carried out on the treatment for refractory and relapsed non-Hodgkin's lymphomas with a combination of two oral topoisomerase II inhibitors, MST-16 and VP-16. On the basis of the synergistic activity in preclinical studies and the schedule dependency in these drugs, low-dose and long-term administration was planned. For the anticipated myelosuppression, two different regimens were designed as an open label trial in this study. In Regimen I, 400 mg of MST-16 combined with 25 mg of VP-16 was administered daily. With this regimen, the response rate (RR)/median time to tumor progression (TTP) in all evaluable patients was 50% (2/4)8.5 months in low grade (indolent) lymphoma and 60% (6/10)/5.2 months in intermediate/high grade (aggressive) lymphomas. In Regimen II, 400 mg of MST-16 combined with 25 mg of VP-16 was administered intermittently (3 days a week or every other day). With this regimen, there was an RR/median TTP of 60% (3/5)/7.0 months in indolent lymphoma and 33.3% (4/12)/1.1 months in aggressive lymphoma. A major side effect in both of these regimens was myelosuppression, with the incidence of grades 3 and 4 toxicity being higher in Regimen I than in Regimen II. The other side effects were uncommon and not severe. These findings indicated that two regimens were tolerated well and were promising for refractory and relapsed aggressive non-Hodgkin's lymphomas. To define the anti-tumor activity and safety of these regimens precisely, large-scale prospective randomized trials are necessary.

A transforming growth factor was found in the extracts of leukemic cells obtained from the peripheral blood of 11 patients with leukemia. This factor stimulated the colony formation of anchorage-dependent BALB c 3T3 cells in soft agar. The high levels of colony-stimulating activities were observed in the cell extracts from patients with chronic myelogenous leukemia in blastic crisis (CML BC), acute myelogenous leukemia and CML in chronic phase. The factor from a CML BC patient was heat- and acid-labile, relatively stable to dithiothreitol treatment and inactivated by pronase treatment. Molecular size of the factor seems more than 10,000 daltons.

The efficacy and safety of sulbactam/cefoperazone (SBT/CPZ) was studied in 94 patients with severe infections and concomitant hematologic diseases. All of the study patients were included in the evaluation for safety, and 76 cases were evaluable for efficacy. Clinical efficacy was excellent in 13 cases (17.1%), good in 27 cases (35.5%), fair in seven cases (9.2%), and poor in 29 cases (38.2%). The bacteriologic eradication was 66.7% for Gram-negative bacilli and 50.0% for Gram-positive bacteria. The efficacy rate for neutropenic patients with counts less than 50 mm3 and 100 mm3 were 47.5 and 42.9%, respectively. Efficacy in patients for whom other antibiotic therapy before treatment with SBT/CPZ had been ineffective was 46.2%. Side effects were reported in one case (1.1%), and abnormal serum liver tests in five cases (5.3%); both returned to normal after discontinuation of the study medication. SBT/CPZ was an effective antibiotic for the treatment of severe infections in the presence of concurrent hematologic diseases.