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W Hiddemann

Publications and source records attributed to W Hiddemann.

At least 91 records · Page 5Linked to original sources
PubMed2001

Pharmacokinetics of cisplatin and relation to nephrotoxicity in paediatric patients.

BACKGROUND: Cisplatin is a highly effective and frequently used drug in the chemotherapy of solid tumours in children, but only limited data are available on the pharmacokinetics of cisplatin and its associated nephrotoxicity in paediatric patients. METHODS: We investigated the pharmacokinetics of free platinum (Pt) in 12 children (25 courses) receiving cisplatin (75-120 mg/m2) either as a continuous 72-h infusion, prolonged single 6-h infusion or repetitive 1-h infusions. Plasma and urinary Pt concentrations were analysed using atomic absorption spectroscopy. Cisplatin-induced nephrotoxicity was determined using creatinine clearance and several glomerular and tubular marker proteins. RESULTS: Using a two-compartment model the pharmacokinetic parameters for free Pt were: initial half-life 21.6 +/- 9.6 min, terminal half-life 25.9 +/- 16.2 h, area under the plasma concentration-time curve (AUC) 13.5 +/- 4.97 (microg/ml) x h/(100 mg/m2) and cumulative renal elimination(infinity) 41.7 +/- 6.6% of dose. Higher cisplatin delivery rates led to higher peak concentrations of free Pt in plasma and urine and to lower cumulative renal Pt elimination (P < 0.01). During all courses, increases of urinary albumin and alpha1-microglobulin excretion were documented. The creatinine clearance decreased significantly to 70% of baseline values. Correlations were found between both peak free Pt concentrations in plasma and in urine and the maximum of urinary excretions of albumin and of N-acetyl-beta-D-glucosaminidase and the nadir of the glomerular filtration rate (P < 0.05). CONCLUSIONS: With respect to nephrotoxicity, long-term infusions of cisplatin seem to be preferable over intermittent bolus administration in paediatric patients. The best predictive pharmacokinetic parameters for cisplatin-associated nephrotoxicity in children are peak free Pt concentrations in plasma and urine.

Adolescent↗
PubMed2001

Efficacy of fludarabine, intermittent sequential high-dose cytosine arabinoside, and mitoxantrone (FIS-HAM) salvage therapy in highly resistant acute leukemias.

Patients with refractory acute leukemias after intensive induction and salvage attempts have a particularly poor prognosis and therapeutic options are limited. In the current study, the pharmacologically based FIS-HAM regimen was applied, which included fludarabine 15 mg/m2 q 12 h (days 1, 2, 8, and 9), cytosine arabinoside as a 45-min infusion every 3 h at 750 mg/m2 per single application (days 1, 2, 8, and 9), and mitoxantrone 10 mg/m2 (days 3, 4, 10, 11). Twenty-six intensively pretreated patients [median age: 38 years; range: 22-65; 16 cases of acute myeloid leukemia (AML) and 10 of acute lymphoblastic leukemia (ALL)] were included. Of 16 patients with AML, 5 achieved a complete remission (CR, 31%), 1 a partial remission (PR, 6%), 2 were nonresponders (13%), and 8 succumbed to early death (ED, 50%). Of 10 patients with ALL, 5 achieved a CR, 1 a PR, 1 was a nonresponder, and 3 died early. Overall, the CR rate was 38%. The median disease-free survival time was 50 days and median survival 90 days. Two patients underwent allogeneic bone marrow transplantation and are alive after 27 and 28 months. Neutropenia amounted to a median of 46 days. Toxicity WHO III/IV included infection (61%), diarrhea (48%), nausea/vomiting (43%), impairment of heart function (30%), and mucositis (26%). The current data indicate a significant activity of FIS-HAM chemotherapy in advanced acute leukemias. However, due to its pronounced toxicity, this regimen should be restricted to third-line therapy for patients expecting a suitable donor for allogeneic transplantation, and supportive treatment should be optimized.

Acute Disease↗
PubMed2001

New insights into the biology of multiple myeloma using a combination of May-Grünwald-Giemsa staining and fluorescence in situ hybridization techniques at the single cell level.

Up to now only limited information is available about the significance of chromosomal aberrations in multiple myeloma (MM) and about the time point of the neoplastic transformation. Fluorescence in situ hybridization (FISH) combined with standard May-Grünwald-Giemsa (MGG) staining or immunophenotyping on a single cell level were applied. Bone marrow (BM) samples were obtained from 11 patients with morphologically proven multiple myeloma. For detection of the chromosomal aberrations, we used FISH on interphase nuclei with commercially available centromere-specific probes for chromosomes 1, 7, 9, 11, 15, and 17 and further DNA probes for 5p13, 5q31, Rb-gene (13q14), cyclin D1 gene (11q13), and p53 gene (17p13). The aberration rate differed between 14% and 71% on bone marrow smears. Using the combination of MGG and FISH we analyzed eight patients. A total of 2622 bone marrow cells were morphologically identified and investigated for their specific chromosomal aberrations. For all probes applied, 57 cells of the erythropoietic lineage, 698 cells of the granulopoietic lineage, and 168 lymphocytes showed two normal FISH signals. Of 1723 nuclei of plasma cells, 464 (26.9%) were also not aberrant, whereas all other nuclei of plasma cells (n=1259, 73%) showed a specific aberration. Combination of fluorescence immunophenotyping and in situ hybridization (FICTION) was applied in 10 of 11 patients. Seventy-eight investigated CD34-positive precursor cells did not show any specific aberration detected before in the plasma cell compartment. In conclusion, the combination of MGG and FISH on a single cell level demonstrated that only plasma cells bore the chromosomal aberration and MM did not evolve at an early cell level.

Adult↗
PubMed2001

Remission induction therapy: the more intensive the better?

Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the postremission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60 years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30 mg/m2 as part of the thioguanine/ AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to demonstrate both in younger and older patients that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6 weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). "The more intensive the better" is certainly not the way to go in the management of AML and other systemic malignancies but some increase in intensity may be possible and better.

Acute Disease↗
PubMed2001

Carboplatin pharmacokinetics in patients receiving carboplatin and paclitaxel/docetaxel for advanced lung cancers: impact of age and renal function on area under the curve.

PURPOSE: To further define the most appropriate way of choosing the dose of carboplatin. PATIENTS AND METHODS: The pharmacokinetics of carboplatin were analyzed in 30 patients with advanced lung cancer receiving a total of 48 cycles of carboplatin plus paclitaxel/ docetaxel combination chemotherapy. Platin concentrations of ultrafiltrated plasma and urine samples were determined by flameless atomic absorption spectrometry. A multiple regression analysis was performed for interactions between pharmacokinetic parameters and pretreatment characteristics. RESULTS: Using a twocompartment-model, the following parameters were obtained (mean, coefficient of variation): initial half-life, 0.903 h (48%); terminal half-life, 13.6 h (116%); maximum plasma concentration (Cmax), 38.5 microM (86%); AUC, 111.9 microM/h (86%); volume of distribution, 411 l (130%); total clearance (Ct), 579 ml/min (75%); renal clearance (Cr), 453 ml/min (80%); renal elimination, 76% of dose (17%). In the univariate analysis, age was significantly related to Cmax (P = 0.0303), AUC (P = 0.0050), Ct (P = 0.0020), Cr (P = 0.0092). Plasma creatinine (Crp) was related to Cmax (P = 0.0228), and 1/[Crp] was related to Cmax (P = 0.0015) and AUC (P = 0.0054), while body weight was related to Cmax (P = 0.0365). No interaction with the schedule of application of the two drugs was observed. In the multivariate analysis, factors significantly related to AUC were 1/[Crp] (P < 0.01) and age (P < 0.01). Crp (P < 0.05) and 1/[Crp] (P < 0.01) were significantly associated with Cmax. CONCLUSIONS: These data stress the importance of dosing carboplatin according to renal function and age and warrant further analyses to validate this concept prospectively.

Adult↗
PubMed2001

Current status and perspectives of therapy for acute myeloid leukemia.

Intensification of induction and postremission chemotherapies has resulted in a steady improvement in outcomes for adults with acute myeloid leukemia (AML) over the past two decades. The global response to initial therapy is now in the range of 60% to 80%, with 20% to 30% of patients experiencing long-term disease-free survival. Modern methodologies have revealed that cytogenetic aberrations are closely related to treatment outcome and have allowed subgroups of patients to be identified who have AML with a good, intermediate, or poor prognosis. The actions and interactions of cytogenetics and therapy in determining treatment outcome have been investigated in a series of clinical trials conducted by the German AML Cooperative Group. Evidence is presented that therapy and cytogenetics can independently influence outcome. It is hoped that our increasing understanding of the biological mechanisms that dictate disease characteristics will lead to improved outcomes for patients with AML.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Gain of an isochromosome 5p: a new recurrent chromosome abnormality in acute monoblastic leukemia.

In acute myeloid leukemia (AML) close associations are known between cytomorphology and cytogenetics such as in AML M3/M3v showing a t(15;17) and in AML M4eo associated with inv(16)/t(16;16). In AML M5 a heterogenous cytogenetic pattern is observed. We describe the gain of an isochromosome of the short arm of chromosome 5 together with the gain of chromosome 8 as the sole abnormalities in two cases of acute monoblastic leukemia. In a third case of acute monoblastic leukemia we also observed the gain of an isochromosome 5p together with trisomy 8. This patient showed in addition an unbalanced translocation between the long arm of chromosome 1 and the short arm of chromosome 14 leading to a trisomy 1q. So far only two cases of AML with i(5)(p10) have been published. In no other hematological malignancy has an isochromosome 5p been reported up to now. As an isochromosome 5p can be misinterpreted as a deletion 5q, which occurs frequently in AML, fluorescence in situ hybridization with loci specific probes is a helpful method to detect this rare abnormality.

Adult↗
PubMed2001

Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk adult soft-tissue sarcomas (STS) of adults: long-term results of a phase II study.

In this phase II study, activity and safety of neoadjuvant regional hyperthermia (RHT) combined with chemotherapy was investigated in 59 patients with primary advanced or recurrent high-risk soft-tissue sarcoma (STS). Patients received four EIA cycles consisting of etoposide, ifosfamide and doxorubicin combined with RHT followed by surgical resection and adjuvant treatment. The overall objective response (OR) rate was 17%, with one complete (2%) and eight partial (15%) responses. In addition, 13 minor responses (25%) were seen. At time of surgery, complete necrosis (pCR) occurred in 6 patients and >75% necrosis (favourable histological response (FHR)) in 12 patients. At the completion of protocol treatment, 36 patients were rendered disease-free which was significantly associated with the initial radiographic and/or pathological tumour response (P=0.004). Treatment-related toxicity was acceptable overall. At a medium follow-up of 82 months, local treatment failure occurred in 33 patients, median overall survival (OS) was 52 months, and the 5-year survival rate was 49% (95% confidence interval (CI): 36-61%). OS which did not differ for extremity versus non-extremity STS (P=0.21) was better for patients responding to EIA combined with RHT (P<0.01).

Adult↗
PubMed2001

Treatment of primary, recurrent or inadequately resected high-risk soft-tissue sarcomas (STS) of adults: results of a phase II pilot study (RHT-95) of neoadjuvant chemotherapy combined with regional hyperthermia.

The efficacy of thermochemotherapy in adult patients with primary, recurrent or inadequately resected non-metastatic high-risk soft-tissue sarcomas (STS) was assessed. 54 patients were prospectively treated with four cycles of etoposide, ifosfamide and doxorubicin (EIA) combined with regional hyperthermia (RHT) followed by surgery, another four cycles of EIA without RHT and external beam radiation. The objective response rate was 16% and at a median follow-up time of 57 months, the 4-year estimated rates of local failure-free survival (LFFS), distant metastasis-free survival (DMFS), event-free survival (EFS) and overall survival (OS) were 59% (95% confidence interval (CI) 45-73%), 59% (95% CI 44-73%), 26% (95% CI 14-38%) and 40% (95% CI 27-53%), respectively. OS was in favour of patients responding to neoadjuvant treatment (P=0.073). In comparison to a preceding phase II study including pre- and postsurgical thermochemotherapy (RHT-91), at a 4-year follow-up the RHT-95 study cohort showed an inferior LFFS rate (P=0.027), but this did not affect DMFS (P=0.558) or OS (P=0.126). Hence, postsurgical thermochemotherapy seems critical for local tumour control without affecting survival.

Adult↗
PubMed2001

Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer.

BACKGROUND: To determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of oxaliplatin administered as hepatic arterial infusion. PATIENTS AND METHODS: Patients with isolated hepatic metastases from colorectal cancer were treated every three weeks with increasing doses of oxaliplatin (4 hours; starting dose 25 mg/m2, escalation in steps of 25 mg/m2) in combination with folinic acid (1 hour, 200 mg/m2) and 5-fluorouracil (2 hour, 600 mg/m2). RESULTS: Twenty-one patients (median age, 61 years) have been entered all of whom are fully evaluable. The DLT has been observed at dose level 6, i.e., at 150 mg/m2/cycle and consisted of leucopenia, obliteration of the hepatic artery, and acute pancreatitis. Overall, toxicity mainly consisted of nausea/vomiting (16 of 21 patients), anemia (16 of 21), upper abdominal pain (15 of 21), sensory neuropathy (10 of 21), diarrhea (9 of 21), and thrombocytopenia (9 of 21). The mean PK parameters were: terminal half-life of ultrafiltrable platin, 17.75 +/- 9.29 hours; renal elimination, 48.7% +/- 14.1% of the applied dose; renal clearance 135.55 +/- 45.32 ml/min. The mean area under the plasma-concentration curve (AUC) increased linearly from 3.22 +/- 0.61 microg x h/ml to 18.45 +/- 8.90 microg x h/ml through the first five dose levels (P = 0.0004). Ten of eighteen evaluable patients achieved a complete or partial response (59%). CONCLUSIONS: The recommended dose for phase II studies is 125 mg/m2 oxaliplatin.

Adult↗
PubMed2001

Weekly docetaxel (Taxotere) in patients with metastatic breast cancer.

BACKGROUND: Docetaxel (Taxotere) has demonstrated high antitumour activity in first- and second-line treatment of metastatic breast cancer. This study analysed the efficacy and toxicity of docetaxel given weekly. PATIENTS AND METHODS: Thirty-five patients with metastatic breast cancer received docetaxel, 35 mg/m2 weekly for six weeks, followed by two weeks without treatment. Additional cycles (three weeks' treatment, two weeks' rest) were given until disease progression. All patients had received prior chemotherapy: 32 and 5 patients had received prior anthracycline-containing and taxane-containing regimens, respectively. Docetaxel was administered for a total of 359 doses (median 9. range 6-22). RESULTS: There was one complete response (3%), 11 partial responses (31%), 17 patients with stable disease (49%) and six with disease progression (17%). Overall response rate was 34% (95% confidential interval (95% CI): 18%-51). Median survival was 307 days; median progression-free survival was 2.6 months (range 1.5 to > or = 5.5 months). Three patients showed grade 3 neutropenia. 14 showed grade 3 alopecia, and various grade 1-2 non-haematological toxicities were observed. Treatment was delayed in two patients due to haematotoxicity. and stopped in one patient due to painful nail toxicity. CONCLUSION: Weekly administration of docetaxel at a dose of 35 mg/m2 is effective and of low toxicity in patients with metastatic breast cancer.

Adult↗
PubMed2001

Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia.

The transcription factor C/EBPalpha (for CCAAT/enhancer binding protein-alpha; encoded by the gene CEBPA) is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and no mature granulocytes are observed in Cebpa-mutant mice. Here we identify heterozygous mutations in CEBPA in ten patients with acute myeloid leukemia (AML). We found that five mutations in the amino terminus truncate the full-length protein, but did not affect a 30-kD protein initiated further downstream. The mutant proteins block wild-type C/EBPalpha DNA binding and transactivation of granulocyte target genes in a dominant-negative manner, and fails to induce granulocytic differentiation. Ours is the first report of CEBPA mutations in human neoplasia, and such mutations are likely to induce the differentiation block found in AML.

Base Sequence↗
PubMed2001

AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia.

The transcription factor CCAAT/enhancer binding protein alpha, or C/EBPalpha, encoded by the CEBPA gene, is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and Cebpa knockout mice exhibit an early block in maturation. Dominant-negative mutations of CEBPA have been found in some patients with acute myeloid leukemia (AML), but not in AML with the t(8;21) translocation which gives rise to the fusion gene RUNX1-CBF2T1 (also known as AML1-ETO) encoding the AML1-ETO fusion protein. RUNX1-CBF2T1 positive-AML blasts had eight-fold lower CEBPA RNA levels and undetectable C/EBPalpha protein levels compared with other subgroups of AML patients. Conditional expression of RUNX1-CBF2T1 in U937 cells downregulated CEBPA mRNA, protein and DNA binding activity. AML1-ETO appears to suppress C/EBPalpha expression indirectly by inhibiting positive autoregulation of the CEBPA promoter. Conditional expression of C/EBPalpha in AML1-ETO-positive Kasumi-1 cells results in neutrophilic differentiation. We suggest that restoring C/EBPalpha expression will have therapeutic implications in RUNX1-CBF2T1-positive leukemias.

Animals↗
PubMed2001

Cytogenetic subgroups in acute myeloid leukemia differ in proliferative activity and response to GM-CSF.

The current study was undertaken to search for differences in the biology of cytogenetic subgroups in patients with de novo acute myeloid leukemia (AML). In addition, factors influencing the metabolism of cytosine arabinoside (araC) as the key agent of antileukemic activity were assessed. Bone marrow aspirates from 91 patients with newly diagnosed AML in whom karyotypes were successfully obtained were analyzed: (1) for spontaneous proliferative activity by 3H-thymidine (3H-TdR) incorporation; (2) proliferative response to GM-CSF by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4-h exposure to 3H-TdR (0.5 microCi/ml); and (3) parameters of araC metabolism comprising 3H-araC uptake in vitro and the activities of polymerase alpha (poly alpha), deoxycytidine kinase (DCK) and deoxycytidine deaminase (DCD). According to the results of chromosome analyses four cytogenetic subgroups were discriminated: (I) normal karyotypes (n = 38); (II) favorable karyotypes [t8;21), t(15;17), inv(16)] (n = 16); (III) unfavorable karyotypes [inv (3), -5, 5q-, t(6;9), +8, t (9;11), complex abnormalities] (n = 20); (IV) karyotypes of unknown prognostic significance (n = 17). Proliferative activity of leukemic blasts was significantly higher in favorable karyotypes (group II) as compared to cases with unfavorable cytogenetics (group III) with median values and range for 3H-TdR uptake in group II of 2.48 pmol/10(5) cells (0.28-25.8) and in group III of 0.51 pmol/10(5) cells (0.04-7.6) (P = 0.0096). The respective values in group I and group IV were 0.7pmol/10(5) cells (0.0-6.7) and 0.98 pmol/10(5) cells (0.0-4.0), respectively. Inversely, response to GM-CSF, as defined by an increase in 3H-TdR incorporation >1.5- fold over control values after 48h of GM-CSF exposure, was significantly lower for patients with a favorable karyotype (group II) as compared to group I (P = 0.04) and group III (P = 0.013). No significant differences between karyotype groups I, II, III and IV were found for 3H-araC incorporation, nor for the activities of poly alpha, DCK and DCD. These data demonstrate differences in the biology of cytogenetic subgroups in AML which may partly explain the well established differences in clinical outcome.

Acute Disease↗
PubMed2001

Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: a study of 90 patients.

The clinical significance of complex chromosome aberrations for adults with acute myeloid leukaemia (AML) was assessed in 920 patients with de novo AML who were karyotyped and treated within the German AML Cooperative Group (AMLCG) trials. Complex chromosome aberrations were defined as three or more numerical and/or structural chromosome aberrations excluding translocations t(8;21)(q22;q22), t(15;17)(q22;q11-q12) and inv(16)(p13q22). Complex chromosome anomalies were detected in 10% of all cases with a significantly higher incidence in patients > or = 60 years of age (17.8% vs. 7.8%, P < 0.0001). Clinical follow-up data were available for 90 patients. Forty-five patients were < 60 years of age and were randomly assigned to double induction therapy with either TAD-TAD [thioguanine, daunorubicin, cytosine arabinoside (AraC)] or TAD-HAM (high-dose AraC, mitoxantrone). Twenty-one patients achieved complete remission (CR) (47%), 20 patients (44%) were non-responders and 9% of patients died during aplasia (early death). The median overall survival (OS) was 7 months and the OS rate at 3 years was 12%. Patients receiving TAD-HAM showed a significantly higher CR rate than patients receiving TAD-TAD (56% vs. 23%, P = 0.04). Median event-free survival was less than 1 month in the TAD-TAD group and 2 months in the TAD-HAM group, respectively (P = 0.04), with a median OS of 4.5 months vs. 7.6 months (P = 0.13) and an OS after 3 years of 7.6% vs. 19.6%. Forty-five patients were > or = 60 years of age: 28 of these patient were treated for induction using one or two TAD courses and 17 cases received TAD-HAM with an age-adjusted reduction of the AraC dose. The CR rate was 44%, 38% were non-responders and 18% experienced early death. The median OS was 8 months and the OS rate at 3 years was 6%. In conclusion, complex chromosome aberrations in de novo AML predicted a dismal outcome, even when patients were treated with intensive chemotherapy. Patients under the age of 60 years with complex aberrant karyotypes may benefit from HAM treatment during induction. However, long-term survival rates are low and alternative treatment strategies for remission induction and consolidation are urgently needed.

Acute Disease↗
PubMed2001

Proliferative activity of leukaemic blasts and cytosine arabinoside pharmacodynamics are associated with cytogenetically defined prognostic subgroups in acute myeloid leukaemia.

The biological mechanisms responsible for the association of specific karyotypes with prognosis in acute myeloid leukaemia (AML) remain largely unclear. A prospective study was performed to evaluate how far cytogenetically defined prognostic subgroups of AML differ in their proliferative activity as a potential mechanism for differential sensitivities to S-phase-specific induction chemotherapy comprising cytosine arabinoside (AraC). One hundred and eighty-seven patients with de novo AML were included in the study; 25 patients with a favourable [inv(16), t(8;21), t(15;17)] karyotype, 99 with a normal karyotype, 29 with an unfavourable karyotype (-5, 5q-, -7, 7q-, complex aberrations) and 34 with cytogenetic aberrations of unknown prognostic significance (all others). The favourable group demonstrated the highest ex vivo proliferative activity (PA) (3.41 pmol/105 cells), significantly (P = 0.02) exceeding the unfavourable group with the lowest PA (0.72) and the group with a normal karyotype (1.06) or with karyotype of unknown significance (1.05) that both demonstrated an intermediate PA. Samples with a high PA (> median of the whole group) were more likely to produce interleukin 3, granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF) (56%, 43% and 50%) than cells with a low PA (33%, 36% and 36%; n.s.). The effect of priming by exogenous GM-CSF or G-CSF was significantly more pronounced in samples with a low PA than in rapidly proliferating samples (P < 0.01). For the whole group, a high PA was closely associated with an increased incorporation of AraC triphosphate (AraCTP) into the DNA (P < 0.0001). Clinically, a high PA was associated with a better complete remission (CR) rate in the normal (95% versus 62%) and the unfavourable group (75% versus 33%). The significant differences in proliferative activity between cytogenetic subgroups of AML are associated with increased cytosine arabinoside pharmacodynamics and constitute one potential mechanism for the different response of cytogenetic subgroups to AraC-based induction therapy.

Adult↗