Characterization of peripheral blood progenitor cells (PBPC) mobilized by filgrastim (rHuG-CSF) in normal volunteers: dose–effect relationship for filgrastim with the character of mobilized PBPC

Filgrastim (rHuG-CSF)-mobilized peripheral blood progenitor cells (PBPC) in healthy Japanese volunteers were characterized in detail using two clonal cell culture systems and double-colour flow cytometry to detect multilineage colony-forming cells and subsets of CD34⁺ cells. The kinetics of PBPC during the administration of filgrastim was studied, and possible differences in the character of progenitor cells relative to given doses of filgrastim were investigated. Filgrastim was administered subcutaneously to normal volunteers for 7 d at doses of 100, 200 or 400 μg/m² (10 per cohort). Treatment with 100 or 200 μg/m² filgrastim was well tolerated; however, the 400 μg/m² dose level was not completed because of bone pain and myalgia. The treatment strikingly mobilized various types of progenitor cells, including highly proliferative megakaryocytic colony-forming cells. The number of progenitor cells peaked on days 5 and 6. The fold increase of circulating progenitor cells from the baseline value in the volunteers treated with 200 μg/m² filgrastim was more pronounced than in those treated with 100 μg/m². Treatment with 200 μg/m² also released the less mature progenitor cells (i.e. mixed colony-forming cells, CD34⁺/33⁻ cells, and CD34⁺/HLA-DR⁻ cells) into circulation better than the 100 μg/m² dose. These results suggest that daily subcutaneous injection with 200 μg/m² filgrastim for 5 d will effectively mobilize, both qualitatively and quantitatively, PBPC in healthy donors.     

CD34+ cell immunoselection from G-CSF-alone-primed peripheral blood in children with low body mass

Summary. We report the data of CD34⁺ cell immunoselection from peripheral blood after G-CSF-alone mobilization (lOμg/kg/d s.c.) in nine children with neuroblastoma (median age 4 5 years (2-8), median body weight 16kg (10-20). Leukaphereses were carried out on a Cobe Spectra separator and two consecutive harvests (4 blood volumes processed) were used for immunoselection on a Ceprate(tm) column. The yield of CD34⁺ cells in the purified fraction was 50% (23-80), with a median number of 2.8xl0⁶ CD34+ cells/kg (1-9-4). All patients were reinfused with selected CD34⁺ cells after busulfan 600 mg/m²+ melphalan 180mg/m² and achieved successful haemopoietic recovery.     

G-CSF after peripheral blood stem cell transplantation in lymphoma patients significantly accelerated neutrophil recovery and shortened time in hospital: results of a randomized BNLI trial

We have undertaken a prospective randomized study in 90 patients with relapsed or resistant lymphomas to assess the value of G-CSF (lenograstim) in the acceleration of myeloid recovery after peripheral blood stem cell transplantation (PBSCT). A common regimen of cyclophosphamide 1.5 g/m² on day 1 and lenograstim 263 μg s.c. on days 2–10 with two aphereses on days 10 and 11 was used for stem cell mobilization. 77% of patients achieved an adequate PBSC collection in two harvests (>2 × 10⁸ MNC/kg or >2 × 10⁶ CD34⁺ cells/kg). 65 patients went on to receive high-dose BEAM chemotherapy and engraftment data was available for 62. 34 patients had been randomized to receive lenograstim 263 μg/d s.c. and 28 to no growth factor. The median time to ANC > 0.5 × 10⁹/l was 9 d in the lenograstim arm versus 12.5 d in the no-lenograstim arm ( P  = 0.0001). This was associated with a median duration of time in hospital post PBSCT of 13 d in the lenograstim arm versus 15.5 d in the no-lenograstim arm ( P  = 0.0002). Median days to platelet independence, platelet transfusions, incidence of infection and red cell transfusion were the same in both arms. These data indicate that lenograstim significantly accelerated myeloid recovery after PBSCT and shortened the duration of hospital stay.     

Intensive chemotherapy with blood progenitor transplantation for primary resistant multiple myeloma

Summary. This study assessed the feasibility and effect of blood progenitors as the only source of haemopoietic support for myeloablative therapy for patients with primary resistant multiple myeloma and markedly infiltrated bone marrow. 17 patients with advanced, primary resistant myeloma received a priming regimen of cyclophosphamide (3 g/m²) and etoposide (900 mg/m²) with GM-CSF. During haematological recovery, at least 2 × 10⁶ CD34⁺ mononuclear cells/kg were collected from each patient with 4-12 leukaphereses. High-dose chemotherapy was then given which consisted of thiotepa (750 mg/m²), busulfan (10 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of the blood progenitors. Haemopoietic reconstitution was rapid with recovery of granulocytes to >1.0 × 10⁹/1 after a median of 10 d and of platelets to 50 × 10⁹/1 after a median of 29 d. The myeloma responded in 10/17 patients for a projected median duration of at least 12 months. Survival was prolonged significantly in comparison with the outcome of control patients who did not receive intensive treatment. Blood progenitors, assessed from the number of CD34⁺ cells, produced early haemopoietic recovery after myeloablative therapy that induced sustained control of advanced and resistant multiple myeloma.     

A pilot study of low-dose recombinant human granulocyte-macrophage colony-stimulating factor in chronic neutropenia

Summary. Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) is under investigation for the treatment of a wide range of haematological disorders. At commonly used doses of > 120 μg/m²/d, extramedullary toxicity is common. We report the effects of low-dose (LD) rhGM-CSF in patients with chronic neutropenia related to HIV infection, myelodysplastic syndrome and idiopathic neutropenia. Nine patients with a mean pre-treatment neutrophil count of 0·6 × 10⁹/1 (range 0·2–1·4 × 10⁹/1) received daily rhGM-CSF at doses of between 5 and 15 μg/m², Eight patients responded with a mean post-treatment ANC of 3·2 × 10⁹/1 (range 1·9–4·6 × 10⁹/1). There was no significant therapy-related morbidity. We conclude that in chronic neutropenia, LD rhGM-CSF is an acceptable treatment which has important cost/benefit implications.     

Randomized clinical study comparing aggressive chemotherapy with or without G-CSF support for high-risk myelodysplastic syndromes or secondary acute myeloid leukaemia evolving from MDS

One hundred and five consecutive primary high-risk myelodysplastic syndromes (MDS) or secondary acute myeloid leukaemia (sAML) evolving from MDS (performance status 0–3, ECOG) entered this study. Induction chemotherapy (CT) consisted of idarubicine 12 mg/m² i.v. on days 1 and 2, etoposide 60 mg/m²/12 h i.v. for 5 d, Ara-C 120 mg/m²/12 h i.v. for 5 d (one or two courses). Patients were randomized to receive or not G-CSF (5 μg/kg/d subcutaneously 48 h after the end of CT). 52 cases underwent CT alone and 53 CT+G-CSF. The CT + G-CSF patients had a significantly shorter duration of neutropenia (8 v 16 d) with a lower incidence of infections and significantly better responses (CR+PR: 74% v 52%, P  < 0.05). 40 patients entered CR: 17 with CT and 23 with CT+G-CSF. Responders underwent two consolidation courses with the same CT, followed by high-dose Ara-C (2 g/m² every 12 h for 3 d). Most CRs were clonal. At present 21 responders have relapsed (median relapse-free survival 4.5 months). Eight responders received an allo-BMT, six are alive in CR 7–57 months post-transplant. Therefore allo-BMT only increases the chance of a long survival and possible cure. In conclusion, CT+G-CSF did not prolong either CR duration or survival; the growth factor support, however, increased the number of allo-transplantable cases by inducing higher remission rates and improving clinical conditions.     

IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II trial

A phase II trial was designed to explore the potential feasibility and efficacy of a reinduction therapy consisting of fludarabine, cytarabine, idarubicin and granulocyte colony stimulating factor (G-CSF) for acute myelogenous leukaemia (AML) patients with poor prognosis.
Twenty-three patients aged 1.2–17.5 years with refractory ( n  = 3), relapsed ( n  = 19) or secondary ( n  = 1) AML were treated with the IDA-FLAG regimen, a combination therapy of idarubicin (days 2–4, 12 mg/m²/d), fludarabine (days 1–4, 30 mg/m²/d), cytarabine (days 1–4, 2000 mg/m²/d) and G-CSF (day 0 up to ANC > 1 × 10⁹/l, 400 μg/m²/d). They received a total of 37 courses of IDA-FLAG and/or FLAG (IDA-FLAG without idarubicin). 17/23 patients achieved a complete remission (CR) with a median duration of 13.5 months (1–39 months), one patient showed a partial remission, and five were nonresponders while in CR, 11 patients underwent bone marrow or PBSC (peripheral blood stem cells) transplantation. Overall, nine patients remain in continuous complete remission with a median duration of 17.5 months (9.5–39 months). The toxicity of the IDA-FLAG courses was more severe than for the FLAG courses with marked neutropenia and thrombocytopenia (for IDA-FLAG: median 22.5 and 25 d respectively; for FLAG: median 10.5 and 14 d respectively). Pulmonary infections were the main nonhaematological toxicity. One patient died in CR from invasive aspergillosis.
The IDA-FLAG regimen produced a CR of >12 months in more than half of the patients and can be recommended as a therapeutic option prior to allogeneic or autologous bone marrow transplantation.     

Peripheral blood stem cell mobilization using high-dose cyclophosphamide and G-CSF in pretreated patients with lymphoma

Summary. Peripheral blood stem cell (PBSC) mobilization for autologous transplantation is more difficult in treated patients and those with bone marrow involvement. In 17 pretreated lymphoma patients, cyclophosphamide (4 g/m²) and G-CSF mobilized a median circulating peak of 1959 CFU-GM/ml on day 12.5. PBSC harvesting commenced when WBC was 1×10⁹/l at day 10.5 collected a median of 21.2 × 10⁴/CFU-GM/kg. 13/17 (76%) patients exceeded the 10 × 10⁴ CFU-GM/kg threshold for engraftment. The CFU-GM yield was significantly higher in patients whose WBC recovered from 1–5 × 10⁹/1 in less than 3 days and correlated with the maximum WBC pre and post the cyclophospharnide induced nadir. This regime safely mobilized adequate PBSC in the majority of pretreated lymphoma patients.     

A randomized phase II study of BB-10010: a variant of human macrophage inflammatory protein-1α for patients receiving high-dose etoposide and cyclophosphamide for malignant lymphoma and breast cancer

Macrophage inflammatory protein-1α (MIP-1α) is a chemokine that can inhibit the cell cycle progression of both primitive haemopoietic and epidermal progenitor cells. This property could potentially be exploited to attenuate both the myelosuppressive effects of chemotherapy as well as mucositis. We evaluated both the biological and clinical effects of BB-10010, a genetically engineered variant of MIP-1α, in patients with malignant lymphoma or breast cancer receiving high-dose etoposide (VP 3.6 g/m²) and cyclophosphamide (Cy 200 mg/kg). 52 patients were randomized to one of three cohorts. Cohort A received no BB-10010; cohorts B and C received 10 μg/kg and 100 μg/kg of BB-10010, respectively. All patients received post-chemotherapy G-CSF. BB-10010 was well tolerated. There were no significant differences between groups in recovery to an ANC > 0.5 × 10⁹/l, 1 × 10⁹/l or 1.5 × 10⁹/l, the number of days with an ANC < 0.5 × 10⁹/l, days to a platelet count >50 × 10⁹/l or 100 × 10⁹/l, or the incidence and severity of mucositis. There was no evidence of any effect of BB-10010 on colony-forming cell (CFC) or long-term culture-initiating cell (LTC-IC) mobilization, cycling activity in the marrow or on chemotherapy-induced changes in CFC or LTC-IC number both of which were in the normal range by 22 d after completion of the chemotherapy. To our knowledge this is the first report of a myelointensive regimen having no apparent long-term effect on the LTC-IC compartment. In summary, BB-10010 is safe when used in patients receiving high-dose therapy but has no effect on reducing the toxicity of such therapy.     

Leucine and Glucose Turnover in Chronic Alcoholics During Early Abstinence and After an Ethanol Load

We studied leucine turnover using a primed infusion of [1-¹⁴C]- l -leucine and glucose turnover using a primed infusion of [6-³H]- d -glucose in five alcoholic patients without liver damage and five age-matched controls. Infusions were maintained for 6 hr, and at the end of the 3rd hour, a 0.8 g/kg iv ethanol load was administered in 20 min. Leucine flux, nonoxidative disposal and oxidation rates, and glucose rate of appearance were calculated during the 3rd and 6th hours of infusion. Ethanol disappearance rate and the percentage completely metabolized to CO₂ and H₂O in 3 hr were also calculated. Compared with controls, alcoholics had significantly higher basal leucine flux (55.6 ± 12 vs. 37.3 ± 9.3 μ m /m²/min) and nonoxidative disposal (48.7 ± 8.7 vs. 31.1 ± 7.5 μ m /m²/min). No differences were observed in basal glucose appearance rates in alcoholics and controls (397.6 ± 115.2 vs. 349.4 ± 120.6 μ m /m²/min). Compared with controls, alcoholics had a higher alcohol disappearance rate (2.72 ± 0.59 vs. 1.84 ± 0.43 m m /kg/min) and percentage of ethanol metabolized to CO₂ and H₂O in 3 hr (40.6 ± 10.2 vs. 22.9 ± 6.9%). After the ethanol load, both leucine turnover and glucose rate of appearance decreased significantly only in alcoholics. There was a positive correlation between the change in leucine flux and ethanol disappearance rate and percentage metabolized to CO₂ and H₂O in alcoholics.     

Haematological reconstitution following high dose and supralethal chemo-radiotherapy using stored, non-cryopreserved autologous bone marrow

S ummary . Eighteen patients with small cell carcinoma of the lung received high dose cyclophosphamide (180–200 mg/kg) intensification following five pulses of 'CHOP' chemotherapy (cyclophosphamide 750 mg/m² i.v., adriamycin 50 mg/m² i.v., vincristine 1·4 mg/m² i.v., prednisolone 40 mg orally for 5 d). They received infusions of autologous bone marrow which had been stored at 4°C for 34 h. Pancytopenia was predictable in onset and its duration acceptable. Recovery of neutrophils to greater than 1·0 × 10⁹/l was achieved in 17·5 ± 0·9 d (mean ± SEM) and platelets to greater than 100 × 10⁹/l in 17·5 ± 0·8 d. Four patients with acute myeloid leukaemia in complete remission received intensification with the supralethal combination of cyclophosphamide and total body irradiation followed by infusion of autologous marrow which had been stored at 4°C for 54 h. Haematological reconstitution in these patients was acceptable but slower (greater than 1·0 × 10⁹/l neutrophils between days 26 and 40; greater than 20 × 10⁹/l platelets between days 23 and 77). Except in one case, normal peripheral counts were attained in all patients.
It is concluded that bone marrow stored at 4°C for up to 54 h is a simple and practical source of viable stem cells which have the capacity for acceptable haematological reconstitution.     

Identification of ''short-lived'' and ''long-lived'' patients at presentation of idiopathic myelofibrosis

Mobilization of Philadelphia chromosome (Ph) negative blood progenitors was attempted in 23 newly diagnosed chronic myeloid leukaemia (CML) patients using a regimen of cyclophosphamide (CY) 5 g/m² and rHUG-CSF 150 μg/m² daily. This regimen was well tolerated with no major adverse events reported. More than 2 × 10⁶/kg CD34⁺ cells were collected in 21 patients (91%). Predominantly Ph-negative mobilization (0–25% Ph-positive) was seen in 30% of cases overall and was confined to patients with a Sokal prognostic score < 1 (7/11 with Sokal score <1; 0/12 with Sokal score ≥1). Within the low Sokal index group, a low WBC count pre-mobilization and a low WBC nadir both correlated strongly with Ph-negative mobilization ( P  =0.006 and 0.02 respectively). Five of 19 patients receiving at least 6 months of Roferon A therapy post mobilization achieved a major cytogenetic response; all five patients were Ph-negative mobilizers. Therefore CML patients can be divided into a good-prognosis group in whom predominantly Ph-negative progenitors can be mobilized using a regimen of moderate intensity if haematological control is achieved pre-mobilization, and a poor-prognosis group for whom predominantly Ph-positive cells are mobilized with this regimen regardless of haematological control.     

Size dependent platelet subpopulations: relationship of platelet volume to ultrastructure, enzymatic activity, and function

A method for the separation of platelets on the basis of their size has been developed using counterflow centrifugation. Platelets were separated, free of plasma proteins and other cells, into seven subpopulations. The smallest-sized platelets, designated as Fraction 1, had a mean platelet volume (MPV) of 3.94 ± 0.60 μm³ (SD). Each successive fraction had a progressively larger MPV. The MPV for the largest-sized platelets, designated Fraction 7, was 8.19 ± 0.64 μm³. The MPV for the original platelets prior to fractionation was 6.57 ± 0.61 μm³. The mean density of Fraction 1 platelets was 1.067 ± 0.002 g/cm³, while Fraction 7 had a mean density of 1.072 ± 0.001 g/cm³. Transmission electron microscopy demonstrated that Fraction 1 had 4.3 ± 0.9 dense bodies per platelet, and Fraction 7 had 12.6 ± 2.4 dense bodies per platelet. Platelet LDH activity showed that the Fraction 1 platelets had 4.77 ± 0.92 iu per 10¹⁰ platelets; Fraction 7 platelets had 14.88 ± 1.23 iu per 10¹⁰ platelets. The LDH activity in the platelets before separation into subpopulations was 9.47 ± 1.45 iu per 10¹⁰ platelets.     

Granulocyte colony-stimulating factor given in addition to interferon-α to mobilize peripheral blood stem cells for autologous transplantation in chronic myeloid leukaemia

In order to potentially mobilize and harvest the Ph⁻ cells observed in most patients with chronic myeloid leukaemia (CML) during interferon-α (IF-α) therapy, G-CSF (filgrastim), 5 μg/kg/d, was administered subcutaneously together with IF-α to 30 CML patients in haematological remission but with various degrees of cytogenetic remission, after IF-α therapy. Peripheral blood stem cells (PBSC ) were harvested using standard aphereses from day 5 of G-CSF. Patients underwent one to four (median three) aphereses. Median total yields/kg were 7.6 (range 3.8–25) × 10⁸ MNC, 3.4 (0–140) × 10⁶ CD34⁺ cells, and 17 (1.1–107) × 10⁴ CFU-GM. No patient had a significant increase in the percentage of Ph⁺ cells in the bone marrow under G-CSF therapy. The percentage of Ph⁺ cells in apheresis products tended to decrease between the first and the last apheresis ( P  = 0.05). 14 patients who were not responsive to IF-α were transplanted after conditioning with busulphan 16 mg/kg and melphalan 140 mg/m². Median time to neutrophils > 0.5 × 10⁹/l was 20 d (16–114 d) and to platelets > 50 × 10⁹/l 18 d (12–149 d). Nine patients had a major cytogenetic response post graft, which correlated with the amount of Ph⁺ cells reinfused with the graft ( P  = 0.02). We conclude that this procedure is feasible, allowing the harvest of enough PBSC, some of them Ph⁻ in patients who responded to IF-α, to allow autologous transplantation.     

Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study

Intensive chemotherapy produces a lower complete remission (CR) rate in the myelodysplastic syndromes (MDS) than in de novo acute myeloid leukaemia (AML), possibly due in part to a higher incidence of P glycoprotein (PGP) expression in MDS blast cells. We designed a randomized trial of intensive chemotherapy with or without quinine, an agent capable of reverting the multidrug resistance (mdr) phenotype, in patients aged  65 years with high-risk MDS. Patients were randomized to receive mitoxantrone 12 mg/m²/d days 2–5 + AraC 1 g/m²/12 h days 1–5, with (Q⁺) or without (Q⁻) quinine (30 mg/kg/d). 131 patients were included. PGP expression analysis was successful in 91 patients. In the 42 PGP-positive cases, 13/25 (52%) patients in the Q⁺ group achieved CR, compared to 3/17 (18%) patients in the Q⁻ group ( P  = 0.02) and median Kaplan-Meier survival was 13 months in the Q⁺ group, and 8 months in the Q⁻ group ( P  = 0.01). No life-threatening toxicity was observed with quinine. In conclusion, the results of this randomized study show that quinine increases the CR rate and survival in PGP-positive MDS cases treated with intensive chemotherapy.     

Low-dose cladribine for symptomatic hairy cell leukaemia

Cladribine is an effective therapy for hairy cell leukaemia (HCL), but the standard regime is frequently complicated by neutropenic fever and prolonged T-cell depression. We studied 102 patients with active HCL following treatment with various doses of cladribine given for 7 d. Two patients received 1 mg cladribine/m²/d without toxicity or effect. Eight subsequent patients received 2 mg cladribine/m²/d, and normalized cytopenia as quickly as 94 control patients receiving a standard dose (3.4mg/m² or 0.085 mg/kg), with significantly less lymphopenia and a similar complete remission rate.     

Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease

Twenty-six patients with relapsed or refractory Hodgkin's disease (HD) were treated with an intensive salvage regimen combining ifosfamide (3000 mg/m²/d, days 1–4 through continuous intravenous infusion) and vinorelbine (25 mg/m², i.v. days 1 and 5) with mesna uroprotection and G-CSF support. Courses were given at 3-week intervals.
Ten patients achieved a complete and 10 patients a partial response, yielding an overall response rate of 77%. The main toxic effect was neutropenia and the combination was well tolerated.     

Treatment of acute myelogenous leukaemia in patients aged 50–65: idarubicin is more effective than zorubicin for remission induction and prolonged disease-free survival can be obtained using a unique consolidation course

From December 1987 to June 1992, 251 patients aged 50–65 with de novo acute myelogenous leukaemia (AML) were recruited to a multi-institutional randomized clinical trial. Induction therapy consisted of Ara-C (200 mg/m², continuous infusion, days 1–7) with either zorubicin (ZRB) (200 mg/m², i.v., days 1–4) or idarubicin (IDR) (8 mg/m², i.v., days 1–5). Consolidation therapy consisted of a single course of intensive chemotherapy with high-dose Ara-C (3 g/m², 3 h infusion, q 12 h, days 1–4) and m-Amsa (100 mg/m²/d, i.v., days 5–7).
The complete remission (CR) rate was (73%) with Ara-C/IDR versus (60%) with Ara-C/ZRB ( P  = 0.033). In multivariate analysis, factors found to be significant in predicting CR were normal karyotype and treatment with IDR. With a median follow-up of 73 months, the median disease-free survival (DFS) duration of all CR patients and the probability of CR at 6 years were 17 months and 29%. In multivariate analysis the only factor associated with an increased DFS duration was a normal karyotype. The median event-free survival (EFS) duration for all evaluable patients and the median overall survival duration for all eligible patients were respectively 7 and 12 months without any difference between induction arms.
The study shows that in patients aged 50–65 idarabicin is more effective than zorubicin for remission induction. However, the type of anthracycline did not influence overall survival duration. Using a unique consolidation course, we observed a prolonged DFS which compares favourably with results obtained with more prolonged consolidation therapy or maintenance treatment.     

Australian Leukaemia Study Group Myeloma II: a randomized trial of intensive combination chemotherapy with or without interferon in patients with myeloma

The Australian Leukaemia Study Group has performed a randomized trial of interferon α-2A (Roferon-A) as a co-induction agent together with intensive combination chemotherapy and as maintenance following completion of 12 cycles of induction treatment. When used as a co-induction agent, interferon-α did not improve response rates, time-to-treatment failure, or overall survival. Patients who had interferon together with intensive combination therapy (PCAB: prednisone 60 mg/m² days 1–5, cyclophosphamide 600 mg/m² day 1, BCNU 30 mg/m² day 1, doxorubicin 30 mg/m² day 1, repeated every 28 d for a total of 12 cycles) had more leucocyte and granulocyte toxicity and received a lower dose intensive of cytotoxic drugs than those patients who received PCAB without interferon.   There was a trend towards prolongation of plateau phase which did not reach significance. Interferon, however, did improve the survival of patients who achieved plateau; for those patients interferon was associated with a 33% decrease in the rate of death after adjusting for initial beta-2 microglobulin level.     

Changes in coagulation and fibrinolysis in childhood ALL: a two-step dose reduction of one E. coli asparaginase preparation

The influence of two different E. coli asparaginase (ASP) preparations on fibrinolytic proteins in childhood ALL was recently reported, demonstrating a clearly significant association between ASP activity and haemostatic changes. Since the Bayer preparation is no longer available for treatment of large series of patients with ALL, the present study was designed to prospectively evaluate coagulation and fibrinolytic changes in leukaemic children receiving different doses of Medac ASP, which is now available for treatment of childhood ALL. Leukaemic children in whom ASP Medac was administered at 3 d intervals in a two-step dose reduction (5000 IU/m², n  = 10; 2500 IU/m², n  = 15) were compared with children who had received Bayer ASP 10 000 IU/m² in the same time schedule in a former randomized trial; at the same venipuncture, blood samples for coagulation studies were obtained before each ASP administration together with serum samples for pharmacoinetic monitoring. Compared with Bayer ASP 10 000 IU/m², patients receiving Medac ASP 5000 IU/m² showed significantly decreased values of fibrinogen, plasminogen, and α2-antiplasmin, along with significantly enhanced thrombin generation. Improvement occurred in children treated with 2500 IU/m² Medac ASP; α2-antiplasmin and D -dimer no longer differed from the Bayer group. Since both patient groups showed complete asparagine depletion during the course of ASP administration, the lower dosage of 2500 IU/m² administered at 3 d intervals should guarantee the specific metabolic therapy for ALL, leading to depletion of the circulating pool of asparagine.