Hans Pralle

Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia.

The purpose of our study was (i) to evaluate the impact of all-trans retinoic acid (ATRA) given as adjunct to chemotherapy and (ii) to compare second consolidation vs maintenance therapy in elderly patients with acute myeloid leukemia (AML). A total of 242 patients aged ⩾61 years (median, 66.6 years) with AML were randomly assigned to ATRA beginning on day +3 after the initiation of chemotherapy (ATRA-arm, n=122) or no ATRA (standard-arm, n=120) in combination with induction and first consolidation therapy. A total of 61 patients in complete remission (CR) were randomly assigned to second intense consolidation (n=31) or 1-year oral maintenance therapy (n=30). After induction therapy the intention-to-treat analysis revealed a significant difference in CR rates between the ATRA- and the standard-arm (52 vs 39%; P=0.05). Event-free (EFS) and overall survival (OS) were significantly better in the ATRA-compared to the standard-arm (P=0.03 and 0.01, respectively). OS after second randomization was significantly better for patients assigned to intensive consolidation therapy (P<0.001). The multivariate model for survival revealed lactate dehydrogenase, cytogenetic risk group, age, and first and second randomization as prognostic variables. In conclusion, the addition of ATRA to induction and consolidation therapy may improve CR rate, EFS and OS in elderly patients with AML.

Risk-adapted postremission therapy in acute myeloid leukemia: results of the german multicenter AML HD93 treatment trial

The objective of the AML HD93 treatment trial was to evaluate the outcome in young adults with acute myeloid leukemia (AML) after postremission therapy was stratified according to cytogenetically defined risk. The rationales for the study design were based (i) on previous favorable results with high-dose cytarabine in AML with t(8;21), inv/t(16q22) and in AML with normal karyotype, and ii) on encouraging results obtained in several phase II trials using autologous stem cell transplantation (SCT). Between July 1993 and January 1998, 223 eligible patients, 16–60 years of age with newly diagnosed AML other than French–American–British type M3/M3v, were entered into the trial. Risk groups were defined as follows: low risk: t(8;21) or inv/t(16q22); intermediate risk: normal karyotype; high risk: all other chromosomal abnormalities. Following intensive double induction therapy with idarubicin, cytarabine and etoposide, all patients in complete remission (CR) received a first consolidation therapy with high-dose cytarabine and mitoxantrone (HAM). A second consolidation therapy was stratified according to the risk group: low risk: HAM; intermediate risk: related allogeneic SCT or sequential HAM; high risk: related allogeneic or autologous SCT. Double induction therapy resulted in a high CR rate of 74.5%, and 90% of the responding patients were eligible for consolidation therapy. Survival for all 223 trial entrants was 40%, and for the 166 patients who entered CR, disease-free (DFS) and overall survival were 40 and 51% after 5 years, respectively. Within the low-, intermediate- and high-risk groups, DFS and survival after 5 years were 62.5 and 87, 40 and 49 and 17 and 26% respectively, without advantage for allogeneic transplantation in the intermediate- and high-risk groups. Postremission therapy-related mortality was 0, 7 and 14%, respectively. This study demonstrates the feasibility of cytogenetically defined risk-adapted consolidation therapy. The overall trial results are at least equivalent to those of published trials supporting the risk-adapted treatment strategy.

Clinical results and pharmacokinetics of high-dose cytosine arabinoside (HD ARA-C).

Four patients with acute nonlymphoblastic leukemia and one malignant teratoma refractory to conventional chemotherapy were treated with high doses of cytosine arabinoside (HD ARA‐C). They received up to 12 cycles of 1.8 to 3 g/m2 every 12 hours applied by 2‐hour infusions. A total of 55 HD ARA‐C infusions was performed. All leukemic patients responded. A complete clearance of blasts from the bone marrow was observed in two patients following 8–12 cycles of 3 g/m2. However, relapses occurred after three and seven weeks, in one case with resistance to HD ARA‐C. The patient with malignant teratoma did not respond. No severe toxicity emerged even after repeated applications. Adverse reactions included moderate nausea and vomiting (4 patients), diarrhea (2 patients), hepatic dysfunction (1 patient), bone pain (1 patient), blurred vision (1 patient), conjunctivitis (1 patient), and exanthema with partial epidermiolysis (1 patient). Granulocytopenia occurring between 3–8 days after having started the therapy, subsided within 4–25 days. Plasma levels of ARA‐C and the metabolite uracil arabinoside (ARA‐U) were monitored. At steady state plasma concentrations of ARA‐C were 32–97 μM (8–24 μ/ml). ARA‐C disappeared from the plasma mono‐ or biphasic with a terminal half‐life (t50%) of 7.8–12.6 minutes. The total clearance (Cl) or ARA‐C varied between 1.7 and 2.9 liters/kg · h, and the distribution volume (Vss) between 0.44 and 0.86 liters/kg. Cerebrospinal fluid (CSF) levels of ARA‐C reached 10–15% of steady state concentrations in plasma.

Neutrophil CD177 (NB1 gp, HNA-2a) expression is increased in severe bacterial infections and polycythaemia vera

The NB1 glycoprotein (CD177, HNA‐2a antigen) is exclusively expressed on human neutrophils. As the clinical significance of CD177 expression is unknown, we investigated its expression in healthy individuals before and after stimulation with granulocyte colony‐stimulating factor (G‐CSF), in patients with rheumatoid arthritis, viral hepatitis, severe bacterial infections and polycythaemia vera. Expression was quantitatively determined by flow cytometry and by real time polymerase chain reaction. Only G‐CSF‐stimulated individuals and patients with severe bacterial infections and polycythaemia showed a significantly (P < 0·001) increased CD177 expression compared with healthy individuals, indicating that neutrophil CD177 expression can increase significantly in certain clinical conditions.

Intensive consolidation versus oral maintenance therapy in patients 61 years or older with acute myeloid leukemia in first remission: results of second randomization of the AML HD98-B treatment trial

Intensive consolidation versus oral maintenance therapy in patients 61 years or older with acute myeloid leukemia in first remission: results of second randomization of the AML HD98-B treatment Trial

Multicentre study on intensified remission induction therapy for acute myeloid leukemia.

In a cooperative study at 13 centres in the Federal Republic of Germany, 213 adult patients with AML were treated for remission induction by a 9-day regimen consisting of cytosine arabinoside, daunorubicin and thioguanine (TAD) according to previously described sequencing. Complete remission was achieved in 70% of all patients. Complete remission rate was 57% in the 49 patients 60 years of age and older and 74% in the 164 patients under 60 years. Sixty-eight per cent of all complete remissions and 75% of those in the higher age group were induced by one induction course. Median survival was 10 months for all patients treated and 16 months for responders. Median remission duration was 13 months with 72 patients still in continuous remission for 1-31 months. Remission duration was not significantly different for patients treated either by monthly maintenance therapy or induction type consolidation without further therapy. However, patients completing two consolidation courses had a significantly longer remission duration of 22 months. Compared to similar multicentre studies on AML therapy the intensified induction regimen applied in this study shows an improvement even in older patients.

Staging systems for multiple myeloma: a comparison.

Summary In 152 patients with multiple myeloma who had been treated with cytostatic agents the prognostic value of seven staging systems was evaluated: (1) Carbone et al (1967); (2) Acute Leukemia Group B (ALGB) and Eastern Cooperative Oncology Group (ECOG) (Costa et al, 1973); (3) Southeastern Cancer Study Group (SECSG) (1975); (4) Durie & Salmon (1975); (5) Alexanian et al (1975); (6) Merlini et al (1980); (7) British Medical Research Council (1980).

Ex vivo antigen preparation for the serological detection of drug-dependent antibodies in immune haemolytic anaemias

Summary. TWO patients with severe, intravascular haemolysis due to drug‐dependent antibodies are described. The antibodies were directed against presumptive metabolites of buthiazide (International Non‐proprietary Name, butizide) and nomifensine. Their detection was possible only in the presence of ex vivo antigens (i.e. fresh serum of volunteers after ingestion of the drugs) while in vitro antigen preparations yielded inconclusive results. Both antibodies lysed normal red cells in the presence of ex vivo antigens and complement. The buthiazide‐related antibody was IgG (subclass IgGl), the nomifensine‐related antibody was IgM. We conclude that the use of ex vivo antigens is of great importance in the serological evaluation of cases with suspected drug‐dependent immune haemolysis.

Successful collection of peripheral blood progenitor cells in patients with acute myeloid leukaemia following early consolidation therapy with granulocyte colony-stimulating factor-supported high-dose cytarabine and mitoxantrone.

We evaluated the feasibility of collecting peripheral blood progenitor cells (PBPC) in patients with acute myeloid leukaemia (AML) following two cycles of induction chemotherapy with idarubicin, cytarabine and etoposide (ICE), and one cycle of consolidation therapy with high‐dose cytarabine and mitoxantrone (HAM). Thirty‐six patients of the multicentre treatment trial AML HD93 were enrolled in this study, and a sufficient number of PBPC was harvested in 30 (83%). Individual peak concentrations of CD34+ cells in the blood varied (range 13.1–291.5/μl; median 20.0/μl). To reach the target quantity of 2.5 × 106 CD34+ cells/kg, between one and six (median two) leukaphereses (LP) were performed. The LP products contained between 0.2 × 106 and 18.9 × 106 CD34+cells/kg (median 1.2 × 106/kg). Multivariate analysis showed that the white blood cell count prior to HAM and the time interval from the start of HAM therapy to reach an unsupported platelet count > 20 × 109/l were predictive for the peak value of CD34+ cells in the blood during the G‐CSF stimulated haematological recovery. In 16 patients an intraindividual comparison was made between bone marrow (BM) and PBPC grafts. Compared to BM grafts, PBPC grafts contained 14‐fold more MNC, 5‐fold more CD34+ cells and 36‐fold more CFU‐GM. A CD34+ subset analysis showed that blood‐derived CD34+ cells had a more immature phenotype as indicated by a lower mean fluorescence intensity for HLA‐DR and CD38. In addition, the proportion of CD34+/Thy‐1+ cells tended to be greater in the PBPC grafts. The data indicate that sufficient PBPC can be collected in the majority of patients with AML following intensive double induction and first consolidation therapy with high‐dose cytarabine and mitoxantrone.

Comparison of β-Thromboglobulin, Flow Cytometry, and Platelet Aggregometry to Study Platelet Activation

This study compares granule membrane protein (GMP)-140 expression measured by flow cytometry, release of beta-thromboglobulin (beta-TG), and platelet aggregometry as markers of platelet activation in vitro. Whole blood was activated with different concentrations of thrombin. There was a significant increase in beta-TG plasma levels after stimulation with 0.01 and 0.04 U thrombin/ml. There was also an increase in GMP-140 expression, but interindividual variability was high. Aggregometry of platelet-rich plasma did not detect platelet activation and formation of platelet aggregates with 0.05 and 0.1 U thrombin/ml, while flow cytometry showed an early and significant increase of GMP-140 expression with these doses. Beta-TG release is a more sensitive marker of platelet activation than GMP-140 while flow cytometry is easier to perform and less susceptible to artifacts.