Bone-marrow transplantations were performed in 71 patients, 11 with panmyelopathy, 17 with recurrence of acute leukaemia, 25 with acute leukaemia and remission, 18 with chronic myeloid leukaemia. The transplantation was allogenic in 67, autologous in 2, isologous in 2. Eight patients each survived in the panmyelopathy and chronic myeloid leukaemia groups. In the group of patients with acute leukaemia only one patient of those in a recurrence survived the transplantation for several years, but after 6 years there was another recurrence. Of the 20 patients with acute myeloid leukaemia who received the transplantation during their first remission, 11 are still alive. Retransplantation because of the recurrence was employed in one case each of acute and chronic myeloid leukaemia. Main cause of death was interstitial pneumonia with an overall risk of 23%. Only 5% of patients developed severe acute graft-versus-host reaction, grades III-IV. The low incidence of this reaction is possibly due to the strict gnotobiotic measures which in most of the patients led to decontamination of the intestinal tract.

There is an increasing demand for platelet transfusions and it remains an ongoing challenge for most blood centers to maintain an adequate platelet inventory. Platelet transfusions doubled in the US and in Canada from 1980 to 1987[1-3]. Between 1989 and 1992 the number of platelet concentrates decreased in the US by 8.9 % while the number of apheresis platelets administered increased by 75 %

In 105 consecutive patients with de novo acute myeloid leukemia (French-American-British M3 excluded), we compared prospectively the risk of bleeding complications, the number of platelet and red blood cell transfusions administered, and the costs of transfusions using two different prophylactic platelet transfusion protocols. Two hundred sixteen cycles of induction or consolidation chemotherapy and 3,843 days of thrombocytopenia less than 25 x 10(9)/L were evaluated. At the start of the study, each of the 17 participating centers decided whether they would use a 10 x 10(9)/L prophylactic platelet transfusion trigger (group A/8 centers) or a 20 x 10(9)/L trigger (group B/9 centers). Bleeding complications (World Health Organization grade 2-4) during treatment cycles were comparable in the two groups: 20 of 110 (18%) in group A and 18 of 106 (17%) in group B (P = .8). Serious bleeding events (grade 3-4) were generally not related to the patient's platelet count but were the consequence of local lesions and plasma coagulation factor deficiencies due to sepsis. Eighty-six percent of the serious bleeding episodes occurred during induction chemotherapy. No patient died of a bleeding complication. There were no significant differences in the number of red blood cell transfusions administered between the two groups, but there were significant differences in the number of platelet transfusions administered per treatment cycle: pooled random donor platelet concentrates averaged 15.4 versus 25.4 (P < .01) and apheresis platelets averaged 3.0 versus 4.8 (P < .05) for group A versus group B, respectively. This resulted in the cost of platelet therapy being one third lower in group A compared with group B without any associated increase in bleeding risk.

Background: Paclitaxel is active in the treatment of patients with metastatic breast cancer (MBC). Preclinical studies showed additive cytotoxicity and non-overlapping toxicity of paclitaxel and 5-fluorouracil (5-FU). Patients and Methods: Pretreated patients with MBC received paclitaxel (3 h i.v.) starting with 125 mg/m(2) and escalating the dose by 25 mg/m(2) steps per dose level up to 200 mg/m(2), followed by a fixed dose of 1,200 mg/m(2) 5-FU (24 h i.v.). Objectives were to determine the maximum tolerated dose (MTD) of paclitaxel and to evaluate the efficacy and safety of this combination. Results: 22 patients entered this trial. For safety analysis 93 treatment cycles were evaluable. The main toxicity was hematological: neutropenia WHO 3+4: 15.0% of cycles, thrombocytopenia WHO 3+4: 4.3% of cycles. Major non hematological toxicities were rare and mostly of WHO grade 1 or 2. Four patients with partial response (response rate 20%) and 8 patients with stable disease were observed. Median time until progression was 13.1 weeks (range 2.3-94.6 weeks). Conclusions: This study indicates a moderate efficacy and good tolerability of paclitaxel in combination with 5-FU in patients with MBC. The MTD of paclitaxel in this combination has not been reached.

In 105 consecutive patients with de novo acute myeloid leukemia (French-American-British M3 excluded), we compared prospectively the risk of bleeding complications, the number of platelet and red blood cell transfusions administered, and the costs of transfusions using two different prophylactic platelet transfusion protocols. Two hundred sixteen cycles of induction or consolidation chemotherapy and 3,843 days of thrombocytopenia less than 25 × 109/L were evaluated. At the start of the study, each of the 17 participating centers decided whether they would use a 10 × 109/L prophylactic platelet transfusion trigger (group A/8 centers) or a 20 × 109/L trigger (group B/9 centers). Bleeding complications (World Health Organization grade 2-4) during treatment cycles were comparable in the two groups: 20 of 110 (18%) in group A and 18 of 106 (17%) in group B (P = .8). Serious bleeding events (grade 3-4) were generally not related to the patient's platelet count but were the consequence of local lesions and plasma coagulation factor deficiencies due to sepsis. Eighty-six percent of the serious bleeding episodes occurred during induction chemotherapy. No patient died of a bleeding complication. There were no significant differences in the number of red blood cell transfusions administered between the two groups, but there were significant differences in the number of platelet transfusions administered per treatment cycle: pooled random donor platelet concentrates averaged 15.4 versus 25.4 (P < .01) and apheresis platelets averaged 3.0 versus 4.8 (P < .05) for group A versus group B, respectively. This resulted in the cost of platelet therapy being one third lower in group A compared with group B without any associated increase in bleeding risk.

This study shows that the 10/nl trigger for prophylactic platelet transfusion according to the inclusion criteria of our transfusion protocol is as safe as the traditional platelet transfusion threshold of 20/nl. The main cause of severe acute bleeding complications in acute myeloid leukemia patients is not the absolute count of thrombocytes but local problems such as gastrointestinal lesions, local infiltrations or hyperleucocytosis and coagulation disorders such as disseminated intravascular coagulopathy during septic shock. A total of 78% of our patients with severe bleeding complications were classified as M4 or M5 (FAB). These myeloid leukemias are often complicated by hyperleucocytosis and local infiltrations. Successful therapeutic management of these problems, beside platelet transfusions, is most important to stop bleeding complications. In no case was the major cause of death fatal bleeding. Our observation confirms the analysis of recent studies in this field.

BACKGROUND:To study intensive postremission therapy in adult patients with acute myeloid leukemia myeloablative therapy followed by allogeneic or unpurged autologous bone marrow transplantation (BMT) was compared with high-dose cytosine-arabinoside/daunorubicin (HDAC) consolidation.PATIENTS AND METHODS:148 de novo AML patients of maximum 50 years (median 36 years, range 16 to 50) were enrolled in the trial. Following induction and early consolidation chemotherapy consisting of daunorubicin, cytosine-arabinoside and VP-16 (DAV), patients with an HLA-identical sibling underwent allogeneic BMT. The other patients received (by randomization or patient's decision) either HDAC or high-dose busulfan plus cyclophosphamide followed by autologous BMT.RESULTS:Hundred and five 105 (70.9%) patients achieved a complete remission. The event-free survival rates after intensive postremission therapy after 72 months were: after BMT (24 patients) 62% (95% confidence interval +/- 19%), after HDAC (44 patients) 36 +/- 16% and after autologous BMT (12 patients) 18 +/- 22%. Thus allogeneic BMT was superior to autologous BMT (p = 0.04), as was HDAC compared to autologous BMT, although not significantly so (p = 0.15). Patients receiving 2 cycles of HDAC had a better 6-year event-free survival rate (47%) and a lower relapse rate (50%) than patients who received only 1 course (29% and 70% respectively).CONCLUSIONS:High-dose busulfan/cyclophosphamide followed by unpurged autologous BMT early after achieving CR had no advantage over high-dose ara-c/daunorubicin. Two cycles of HDAC yielded better results than 1 cycle. The highest event-free survival rate was reached with myeloablative therapy followed by allogeneic BMT.

In a randomized, phase II trial, we evaluated the effectiveness of continued chemotherapy with epirubicin/ ifosfamide versus unmaintained treatment interruption in advanced metastatic breast cancer. Three hundred fifty-seven patients were enrolled and 331 were evaluable for response. Complete response was achieved in 25 patients (8%) and partial response in 121 patients (37%). Pretreatment status correlated significantly with response (complete and partial response). While 54% of unpretreated patients responded, only 42% of the patients responded who had been pretreated with adjuvant chemotherapy and 33% who had been pretreated in the metastatic stage of disease; 69 patients (21%) had disease progression. Of 11 patients pretreated in both the adjuvant and metastatic setting, only two responded. Toxicity of treatment was mild, with leukopenia being the treatment-limiting factor. Thrombocyte levels were not altered significantly by treatment. Thus, there seems to be room for dose escalation using granulocyte colony-stimulating factor. There was no considerable cardiotoxicity, central nervous system toxicity, or cystitis observed. The low rate of cardiotoxicity appeared to be related to dose fractionation of epirubicin. After randomization of patients to treatment interruption versus continuation of chemotherapy, a longer relapse-free survival was observed for patients who continued chemotherapy (mean relapse-free survival, 2+ months); however, this did not translate into prolonged survival. The cumulative scores of toxicity and quality of life parameters showed increasing superiority for treatment interruption. Therefore, a strategy of treatment until maximum response and subsequent treatment interruption seems to be superior to treatment continuation.

Background. To study intensive postremission therapy in adult patients with acute myeloid leukemia myeloablative therapy followed by allogeneic or unpurged autologous bone marrow transplantation (BMT) was compared with high-dose cytosine-arabinoside/daunorubicin (HDAC) consolidation. Patients and methods: 148 de novo AML patients of maximum 50 years (median 36 years, range 16 to 50) were enrolled in the trial. Following induction and early consolidation chemotherapy consisting of daunorubicin, cytosine-arabinoside and VP-16 (DAV), patients with an HLA-identical sibling underwent allogeneic BMT. The other patients received (by randomization or patient's decision) either HDAC or high-dose busulfan plus cyclophosphamide followed by autologous BMT. Results: Hundred and five 105 (70.9%) patients achieved a complete remission. The event-free survival rates after intensive postremission therapy after 72 months were: after BMT (24 patients) 62% (95% confidence interval +/- 19%), after HDAC (44 patients) 36 +/- 16% and after autologous BMT (12 patients) 18 +/- 22%. Thus allogeneic BMT was superior to autologous BMT (p = 0.04), as was HDAC compared to autologous BMT, although not significantly so (p = 0.15). Patients receiving 2 cycles of HDAC had a better 6-year event-free survival rate (47%) and a lower relapse rate (50%) than patients who received only 1 course (29% and 70% respectively). Conclusions: High-dose busulfan/cyclophosphamide followed by unpurged autologous BMT early after achieving CR had no advantage over high-dose ara-c/daunorubicin. Two cycles of HDAC yielded better results than 1 cycle. The highest event-free survival rate was reached with myeloablative therapy followed by allogeneic BMT.

Background: Anemia in patients with myelodysplastic syndromes (MDS) is usually put down to ineffective erythropoiesis, although the contributory role of other mechanisms has not been sufficiently understood until now. Evidence has been found that in some cases of MDS erythropoietin (EPO) is able to restore anemia to a certain extent. Especially in cases of MDS with a relatively good prognosis, such as refractory anemia (RA) and refractory anemia with ring sideroblasts (RARS), a benefit may be expected for patients treated with EPO since blood transfusion and its associated risks could be spared or at least markedly reduced.Patients and Methods: In a phase II study a total of 26 patients was recruited (female 15, male 11; median age 72 years), 15 patients with RA and 11 patients with RARS were initially treated with 5,000 IU EPO s.c. daily for 4 weeks, In case of response, treatment was continued up to 24 weeks; in case of nonresponse, the EPO dose was augmented to 10,000 IU s.c. for a further 4 weeks. If there was still no response, treatment was stopped, otherwise it was continued up to 24 weeks. Treatment response was defined as an increase of hemoglobin by at least 2 g/dl with unchanged transfusion rate or a major reduction of transfusion rate by at least 30%.Results: 26 patients were evaluable. 5 patients - 2 with RA, 3 with RARS - responded with a major reduction of transfusion rate (>30%) to therapy with 10,000 IU EPO daily. 5 patients showed a minor response (<30%). No patient showed a significant increase of Hb (>2 g/dl). In 2 patients treatment had to be stopped. Two of the responding patients showed elevated endogenous serum EPO levels (>200 U/l) prior to therapy.Conclusion: EPO shows an effective reduction of transfusion rates in MDS patients with RA or RARS in only 25%. Thus it cannot be generally recommended, Response to treatment may occur even if initial endogenous EPO levels are markedly increased.

A total of 149 consecutive de novo AML patients aged 50 years or less (median age = 37 years) were enrolled in this prospective multicenter trial initiated in May 1985. All patients received the same induction and early consolidation therapy with daunorubicin (DNR), cytosine arabinoside (Ara-C), and etoposide (DAV). High-dose Ara-C/DNR therapy included Ara-C at 3 g/m2, in 12 doses (HD-Ara-C/DNR I) and eight doses (HD-Ara-C/DNR II), followed by DNR 30 mg/m2 for 3 days. A complete remission (CR) was achieved in 104 (70%) patients; 61 complete responders received at least one cycle with HD-Ara-C/DNR. If those patients who were transplanted in first CR (n = 26), were not considered, the median relapse-free-survival (MRFS) of the remaining 78 patients was 15 months, with a probability of relapse-free survival (RFS) at 116 months of 30% (95% CI, 20-40%) after a median follow-up of 95 months. The MRFS of the HD-Ara-C/DNR consolidated patients was 25 months, with a probability of RFS at 116 months of 37% (95% CI, 24-50%). If all patients who were transplanted (n = 44) were not considered, the median survival time (MST) was 18 months with a probability of being alive at 118 months of 24% (95% CI, 16-33%). MST of the HD-Ara-C/DNR consolidated patients was 58 months with a survival probability of 46% (95% CI, 31-60%) at 118 months. Prognostic factor analysis did not reveal any significant influence of age, sex, FAB subtype, white blood cell count, hemoglobin level, thrombocyte count, LDH, or response to the first induction course on RFS of the HD-Ara-C/DNR consolidated patients. In summary, HD-Ara-C/DNR consolidation can improve the long-term outcome of a subgroup of de novo AML patients. Further improvement of the outcome seems to depend on the identification of patients with an inferior outcome under that strategy who might benefit from alternative treatment strategies.