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T Büchner

Publications and source records attributed to T Büchner.

At least 37 records · Page 2Linked to original sources
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

Spectral karyotyping and fluorescence in situ hybridization detect novel chromosomal aberrations, a recurring involvement of chromosome 21 and amplification of the MYC oncogene in acute myeloid leukaemia M2.

Recurring chromosomal aberrations are of aetiological, diagnostic, prognostic and therapeutic importance in acute myeloid leukaemia (AML). However, aberrations are detected in only two thirds of AML cases at diagnosis and recurrent balanced translocations in only 50%. Spectral karyotyping (SKY) enables simultaneous visualization of all human chromosomes in different colours, facilitating the comprehensive evaluation of chromosomal abnormalities. Therefore, SKY was used to characterize 37 cases of newly diagnosed AML-M2, previously analysed using G-banding. In 15/23 patients it was possible to obtain metaphases from viably frozen cells; in 22 additional cases, fixed-cell suspensions were used. Of the 70 chromosomal aberrations identified by SKY, 30 aberrations were detected for the first time, 18 aberrations were redefined and 22 were confirmed. SKY detected two reciprocal translocations, t(X;3) and t(11;19). In five cases, eight structural aberrations resulted in partial gains of chromosome 21, six of which were undetected by G-banding. In 4/5 cases, these resulted in copy number increases for AML1. Amplification of MYC was detected in three cases. Using SKY and FISH, clonal aberrations were identified in 5/18 cases with a presumed normal karyotype; 3/5 aberrations were of known unfavourable prognostic significance. Karyotypes were entered into a custom-designed SKY database, which will be integrated with other cytogenetic and genomic databases.

Chromosome Aberrations↗
PubMed2001

Acute myeloid leukaemia (AML): treatment of the older patient.

Undertreatment of the older patients with acute myeloid leukaemia (AML) can explain, in part, their inferior outcome when compared with that of younger patients. Corresponding to the benefit to patients under the age of 60 from high-dose Ara-C there are also dose effects in those over 60 years old, in particular for daunorubicin in the induction treatment, and for the quantity in terms of duration of postremission treatment. The use of these effects can partly overcome the mostly unfavourable disease biology seen in older age AML patients, which is expressed by the absence of favourable and the over-representation of adverse chromosomal abnormalities as well as by the expression of drug resistance. We recommend an adequate dosage of 60 mg/m(2)daunorubicin for 3 days in combination with standard dose Ara-C and 6-thioguanine given for induction and consolidation, followed by a prolonged monthly maintenance chemotherapy for a duration of at least 1 year. Further improvements in supportive care may help in delivering additional anti-leukaemic cytotoxicity. As a novel approach, non-myeloablative preparative regimens may open up the field of allogeneic transplantation for older patients with AML. Given that the actual median age in this disease is more than 60 years the management of older age AML remains as the major challenge.

Acute Disease↗
PubMed2000

Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways.

Somatic mutations of the receptor tyrosine kinase Flt3 consisting of internal tandem duplications (ITD) occur in 20% of patients with acute myeloid leukemia. They are associated with a poor prognosis of the disease. In this study, we characterized the oncogenic potential and signaling properties of Flt3 mutations. We constructed chimeric molecules that consisted of the murine Flt3 backbone and a 510-base pair human Flt3 fragment, which contained either 4 different ITD mutants or the wild-type coding sequence. Flt3 isoforms containing ITD mutations (Flt3-ITD) induced factor-independent growth and resistance to radiation-induced apoptosis in 32D cells. Cells containing Flt3-ITD, but not those containing wild-type Flt3 (Flt3-WT), formed colonies in methylcellulose. Injection of 32D/Flt3-ITD induced rapid development of a leukemia-type disease in syngeneic mice. Flt3-ITD mutations exhibited constitutive autophosphorylation of the immature form of the Flt3 receptor. Analysis of the involved signal transduction pathways revealed that Flt3-ITD only slightly activated the MAP kinases Erk1 and 2 and the protein kinase B (Akt) in the absence of ligand and retained ligand-induced activation of these enzymes. However, Flt3-ITD led to strong factor-independent activation of STAT5. The relative importance of the STAT5 and Ras pathways for ITD-induced colony formation was assessed by transfection of dominant negative (dn) forms of these proteins: transfection of dnSTAT5 inhibited colony formation by 50%. Despite its weak constitutive activation by Flt3-ITD, dnRas also strongly inhibited Flt3-ITD-mediated colony formation. Taken together, Flt3-ITD mutations induce factor-independent growth and leukemogenesis of 32D cells that are mediated by the Ras and STAT5 pathways. (Blood. 2000;96:3907-3914)

Acute Disease↗
PubMed2000

Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia.

The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (x500 field, 0.126 mm(2)) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/x500 field vs 11.2 (10. 0-12.0)/x500 field, respectively (P <.001). On day 16 of induction chemotherapy, microvessel density was reduced by 60% (44-66) (P <. 001) in hypoplastic marrows without residual blasts, in contrast to only 17% (0-37) reduction in hypoplastic marrows with >/= 5% residual blasts (P <.001 for the difference between both groups). Bone marrow biopsies taken at the time of complete remission displayed a microvessel density in the same range as the controls. In conclusion, there is evidence of increased microvessel density in the bone marrow of patients with AML, which supports the hypothesis of an important role of angiogenesis in AML. Furthermore, these findings suggest that antiangiogenic therapy might constitute a novel strategy for the treatment of AML. (Blood. 2000;95:2637-2644)

Acute Disease↗
PubMed2000

Effective ex vivo generation of megakaryocytic cells from mobilized peripheral blood CD34(+) cells with stem cell factor and promegapoietin.

OBJECTIVE: The additional transplantation of ex vivo-generated megakaryocytic cells might enable the clinician to ameliorate or abrogate high-dose chemotherapy-induced thrombocytopenia. Therefore, the ex vivo expansion of CD34(+) PBPC was systematically studied aiming for an optimum production of megakaryocytic cells. MATERIALS AND METHODS: CD34(+) PBPC were cultured in serum-free medium comparing different (n = 23) combinations of stem cell factor (SCF) (S), IL-1beta (1), IL-3 (3), IL-6 (6), erythropoietin (EPO) (E), thrombopoietin (TPO) (T) and promegapoietin (PMP, a novel chimeric IL-3/TPO receptor agonist). Ex vivo-generated cells were assessed by flow cytometry, morphology, and progenitor cell assays. RESULTS: Addition of TPO to cultures stimulated with S163E, a potent progenitor cell expansion cocktail previously described by our group, effectively induced the generation of CD61(+) cells (day 12: 31.4 +/- 7.9%). The addition of PMP tended to be more effective than TPO +/- IL-3. Whereas EPO was not required to maximize TPO- or PMP-induced megakaryocytic cell production, the use of IL-6 and IL-1beta augmented cellular expansion as well as CD61(+) cell production rates in the majority of cytokine combinations studied. Thus, the most effective CD61(+) cell expansion cocktail consisted of S163 + PMP which resulted in 65.9 +/- 3.0% CD61(+) at day 12 and an overall production of 40.7 +/- 4.5 CD61(+) cells per seeded CD34(+) PBPC. However, the basic 2-factor combination S + PMP also allowed for an effective CD61(+) cell production (day 12 CD61(+) cell production: 15.1 +/- 1.6). Moreover, maximum amplification of CFU-Meg was observed after 7 days using this two-factor cocktail (12.9 +/- 2.6-fold). The majority of CD61(+) cells generated in TPO- or PMP-based medium were low-ploidy 4N and 8N cells, and ex vivo-generated CD61(+), CD41(+), and CD42b(+) cells were mainly double positive for FACS-measured intracellular von Willebrand Factor (vWF) (76.7 +/- 3.3%, 58.8 +/- 4.4%, and 82.7 +/- 2.5%, respectively). CONCLUSIONS: Taken together, this study demonstrates that megakaryocytic cells can be effectively produced ex vivo with as little as two-factors (SCF + PMP), an approach that might be favorably employed in a clinical expansion trial aiming to ameliorate high-dose chemotherapy-induced thrombocytopenia.

Cell Differentiation↗
PubMed2000

Multivariate analysis of prognostic factors in patients with refractory and relapsed acute myeloid leukemia undergoing sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy: relevance of cytogenetic abnormalities.

To improve the basis for the stratification of patients with refractory and relapsed acute myeloid leukemia (AML) univariate and multivariate analyses of prognostic factors were performed in 254 patients (median age 50 years, range 18-74) undergoing S-HAM salvage chemotherapy during two consecutive prospective trials of the German AML Cooperative Group. In a multivariate analysis, duration of the first complete remission (CR) was the only factor associated with time to treatment failure (P = 0.0223). Disease-free survival was influenced by a short duration of the first CR of less than 6 months (P = 0.0001), WBC (P = 0.0018), blast count (P = 0.0037), and neutrophil count (P = 0.0119). The achievement of CR was related to the hemoglobin level only (P = 0.0457), the early death rate was related to age only (P = 0.0109), and survival was related to the bilirubin level only (P = 0.0166). In the subgroup of 104 patients in whom additional karyotype analyses were performed prior to first-line therapy unfavorable chromosome abnormalities were associated with a lower CR rate (univariate analysis, P = 0.0342; CR 24% vs 53%) and were the only factor related to survival. These analyses warrant the further evaluation of the impact of cytogenetic abnormalities on the outcome of patients with advanced AML in order to improve the characterization according to duration of first CR and to WBC of distinct subgroups of patients with differing prognoses as a basis for stratification in future trials.

Adult↗
PubMed2000

Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML.

Partial tandem duplications of the MLL gene have been associated with trisomy 11 in acute myeloid leukemia (AML) and recently, have also been reported for karyotypically normal AML. In order to test the incidence and prognostic importance of this molecular marker, we have analyzed eight cases of AML with trisomy 11 and 387 unselected consecutive cases with AML for partial duplications of the MLL gene. Patients with normal karyotypes and those with various chromosome aberrations were included. De novo as well as secondary leukemias including all FAB subtypes were analyzed. Performing a one-step RT-PCR with 35 cycles using an exon 9 forward primer and an exon 3 reverse primer partial tandem duplications of the MLL gene were demonstrated in 3/8 (37.5%) patients with trisomy 11. In addition, 13/387 (3.4%) of unselected cases revealed a tandem duplication. Ten of these 13 cases were cytogenetically normal, the other three cases had < or =2 additional chromosomal alterations. Sequencing of the RT-PCR products of all 16 positive cases revealed fusions of MLL exon 9/exon 3 (e9/e3) (six cases), e10/e3 (three cases), e11/e3 (four cases) or combinations of differentially spliced e10/e3 and e11/e3 (three cases) transcripts. The duplications were confirmed by genomic long range PCR and Southern blot hybridization. Twelve cases with the MLL duplication were de novo myeloid leukemia, one was a secondary AML after MDS, three were therapy-related AML (t-AML). Of the 16 MLL-duplication positive cases, seven were classified as FAB M2, two as M1, five as M4, one as M0, one as M5b. The mean age was 62.3 years for patients with MLL duplication vs 50.3 years for the control group. Of 15 adult patients, 12 received treatment. Of these, three were nonresponders, five had early relapse (< or =6 months), four relapsed between 7 and 12 months. Median survival and relapse-free interval of the MLL duplication positive group was significantly worse than those of an age-matched karyotypically normal control group. In conclusion, MLL tandem duplications (1) are less common than previously reported; (2) are preferentially observed in AML with normal karyotypes, but can also be found in the presence of chromosome alterations; (3) are not strongly associated with an FAB subtype; (4) were not observed with the prognostically favorable t(8;21), inv(16), and t(15;17), other recurrent translocations, or in complex karyotypes; and (5) identifies a subgroup of patients with an unfavorable prognosis.

Aged↗
PubMed2000

Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. German AML Cooperative Group.

A prospective multicenter study was performed to investigate the clinical and molecular results of intensified double induction therapy including high-dose cytarabine (ara-C) in combination with ATRA in newly diagnosed acute promyelocytic leukemia (APL), followed by consolidation and 3 years maintenance therapy. Fifty-one patients, diagnosed and monitored from December 1994 to June 1999, were evaluated. The median age was 43 (16-60) years. The morphologic diagnosis was M3 in 40 (78%) and M3v in 11 (22%) patients. In 15 (30%) patients the initial white blood cell counts were > or =5 x 10(9)/l. The cytogenetic or molecular proof of the translocation t(15;17) was a mandatory prerequisite for eligibility. The diagnosis was confirmed by karyotyping in 46 and by RT-PCR of the PML/RARalpha transcript in 45 cases. The rate of complete hematological remission was 92% and the early death rate 8%. Monitoring of minimal residual disease by RT-PCR of PML/RARalpha (sensitivity 10(-4)) showed negativity in 29 of 32 (91%) evaluable cases after induction, in 23 of 25 (92%) after consolidation, and in 27 of 30 (90%) during maintenance, after a median time of 2, 4 and of 18 months after diagnosis, respectively. After a median follow-up of 27 months, the estimated actuarial 2 years overall and event-free survival were both 88% (79, 97), and the 2 years relapse-free survival 96% (90, 100). The high antileukemic efficacy of this treatment strategy is demonstrated by a rapid and extensive reduction of the malignant clone and by a low relapse rate. The results suggest that the intensity of the induction chemotherapy combined with ATRA is one of the factors which may have a critical influence on the outcome of APL. A randomized trial should assess the value of an induction therapy including ATRA and high-dose ara-C in comparison to standard-dose ara-C.

Adolescent↗
PubMed2000

Amplification of the MLL gene on double minutes, a homogeneously staining region, and ring chromosomes in five patients with acute myeloid leukemia or myelodysplastic syndrome.

Gene amplification is one of the mechanisms for activating proto-oncogenes resulting in an enhanced expression of the corresponding gene product. By fluorescence in situ hybridization (FISH), amplification of the proto-oncogene MLL has been described only in seven patients with acute myeloid leukemia (AML). We report five new patients (four had de novo AML, one had a de novo myelodysplastic syndrome) displaying different mechanisms of MLL amplification, suspected by G-banding and confirmed by FISH analysis. In two patients, MLL was amplified on double-minute chromosomes (dmins). In both cases, an interstitial deletion in 11q23 including the MLL gene was associated with the occurrence of the dmins containing MLL. As a rarely described mechanism, MLL amplification in the form of size-variable ring chromosomes was observed in two patients. Remodeling of the ring chromosomes leads to multiple copies of MLL and obviously provided a selective growth advantage. In one of the two cases with ring chromosomes, the centromeric alpha-satellite DNA of the ring chromosome was not detectable. Our fifth patient showed the unique finding of MLL amplification within a uniformly (homogeneously?) stained region in interaction with amplified ribosomal DNA sequences. Also, one of the patients with ring chromosomes exhibited the amplification of ribosomal DNA on the ring chromosomes. The transcriptionally active genes for ribosomal RNA could probably enhance the expression of MLL. In one of our five patients, we found the new combination of concomitant amplification of the proto-oncogenes MLL and MYC.

Adult↗
PubMed2000

Clinical significance of P-glycoprotein expression and function for response to induction chemotherapy, relapse rate and overall survival in acute leukemia.

BACKGROUND AND OBJECTIVES: A multidrug-resistance (MDR) phenotype mediated by P-glycoprotein (P-gp) contributes to chemotherapy failure in acute leukemia. However, the exact prognostic significance of this resistance mechanism is still unclear, mostly due to methodologic problems in P-gp detection. We therefore investigated, whether P-gp expression levels or functional P-gp activity better predict response to induction chemotherapy, relapse rate and overall survival in acute leukemia. DESIGN AND METHODS: We examined cell samples of 121 adults with de novo acute myeloid leukemia (AML) and 102 children with newly diagnosed acute lymphoblastic leukemia (ALL) for P-gp expression and functional P-gp activity by flow cytometry. P-gp function was determined by the rhodamine 123 (rh123)-efflux test (AML n=121, ALL n=102) and P-gp expression levels using the P-gp specific monoclonal antibodies (moabs) MRK-16 (AML n=51, ALL n=31), 4.E3 (AML n=35, ALL n=32), or UIC-2 (AML n=68, ALL n=50). We correlated our findings with the immunophenotype, FAB morphology, cytogenetics and clinical data of the examined patients. RESULTS: P-gp expression levels as detected by MRK-16 and 4.E3 were very low and did not differ between AML and ALL as estimated using relative fluorescence intensity (RFI) values and D-values by Kolmogorow-Smirnov (KS) statistics. For moab UIC-2, P-gp expression levels were higher in AML than in ALL. Within AML, moab UIC-2 mainly reacted with myelomonocytic-differentiated leukemic cells of the FAB M4/5 subtypes. No correlation between P-gp expression levels as detected by MRK-16, 4.E3 or UIC-2 and the response to induction chemotherapy or relapse rate, both in AML and ALL, was observed. However, a prognostic impact of P-gp expression levels on overall survival in AML was seen for moab MRK-16. Moreover, within AML, P-gp function was higher in immature blast cells as defined by immunophenotype and FAB morphology and correlated with response to induction chemotherapy, relapse rate, overall survival as well as cytogenetic risk groups. In ALL, the overall functional P-gp activity was lower than in AML and did not correlate with immunophenotypical subgroups, response to induction chemotherapy, relapse rate or overall survival. INTERPRETATION AND CONCLUSIONS: Our data demonstrate a prognostic impact of P-gp in AML but not ALL and indicate that the functional rh123-efflux assay should be preferred for flow-cytometric P-gp evaluation in acute leukemia compared with P-gp expression analysis by monoclonal antibodies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Acute myeloid leukemia in adults: is postconsolidation maintenance therapy necessary?

Maintenance treatment for patients with acute myeloid leukemia (AML) in remission has recently been controversially discussed and even abandoned by several groups. An analysis of 14 recently published multicenter trials, however, revealed the highest probabilities of relapse-free survival (RFS), in the range of 35% to 42% at 4 to 5 years, only in patients assigned to maintenance treatment as far as adult age and intent-to-treat conditions were considered. After having demonstrated a superior RFS rate from 3 years of maintenance after standard-dose consolidation compared with that from consolidation alone (P = .00004), the German AMLCG requestioned the effect of maintenance randomly compared with sequential high-dose cytosine arabinoside (Ara-C) and mitoxantrone in patients who received intensified induction treatment. The results show an advantage for maintenance treatment (RFS rate of 32%) versus the sequential Ara-C and mitoxantrone treatment (RFS rate of 25%) (P = .021). We conclude that maintenance treatment continues to substantially contribute to the management of adult patients with AML, even as part of recent strategies using intensified induction treatment, and thus appears necessary in these settings.

Acute Disease↗
PubMed1999

Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group.

Early intensification of chemotherapy with high-dose cytarabine either in the postremission or remission induction phase has recently been shown to improve long-term relapse-free survival (RFS) in patients with acute myeloid leukemia (AML). Comparable results have been produced with the double induction strategy. The present trial evaluated the contribution of high-dose versus standard-dose cytarabine to this strategy. Between March 1985 and November 1992, 725 eligible patients 16 to 60 years of age with newly diagnosed primary AML entered the trial. Before treatment started, patients were randomized between two versions of double induction: 2 courses of standard-dose cytarabine (ara-C) with daunorubicin and 6-thioguanine (TAD) were compared with 1 course of TAD followed by high-dose cytarabine (3 g/m2 every 12 hours for 6 times) with mitoxantrone (HAM). Second courses started on day 21 before remission criteria were reached, regardless of the presence or absence of blast cells in the bone marrow. Patients in remission received consolidation by TAD and monthly maintenance with reduced TAD courses for 3 years. The complete remission (CR) rate in the TAD-TAD compared with the TAD-HAM arm was 65% versus 71% (not significant [NS]), and the early and hypoplastic death rate was 18% versus 14% (NS). The corresponding RFS after 5 years was 29% versus 35% (NS). An explorative analysis identified a subgroup of 286 patients with a poor prognosis representing 39% of the entire population; they included patients with more than 40% residual blasts in the day-16 bone marrow, patients with unfavorable karyotype, and those with high levels of serum lactate dehydrogenase. Their CR rate was 65% versus 49% (p =.004) in favor of TAD-HAM and was associated with a superior event-free survival (median, 7 v 3 months; 5 years, 17% v 12%; P =.012) and overall survival (median, 13 v 8 months; 5 years, 24% v 18%; P =.009). This suggests that the incorporation of high-dose cytarabine with mitoxantrone may contribute a specific benefit to poor-risk patients that, however, requires further substantiation. Double induction, followed by consolidation and maintenance, proved a safe and effective strategy and a new way of delivering early intensification treatment for AML.

Adolescent↗
PubMed1999

[Treatment of adult acute lymphoblastic leukemia].

In patients with adult ALL, substantial progress has been made in the past 20 years. At present a cure rate of 30-40% can be achieved and varies in defined subgroups between 10-51%. ALL does not represent an uniform disease but is formed by biologic subentities, which differ in their natural history, clinical presentation and prognosis. A comprehensive diagnostic examination, including morphology, cytochemistry, immunology, cytogenetic and molecular genetic analysis is a precondition for prognostic assessment and therapeutic stratification. The basic principle of ALL treatment is a combination chemotherapy with sequential administration of induction, consolidation and maintenance therapy. Bone marrow transplantation has become an important part of the treatment strategy and is performed in patients with high risk. In the subgroup of T-ALL a significant progress has been made in the last years with survival rates of 40-50%. In B-ALL the results have been greatly improved to 48-51% by introduction of a specific treatment strategy. However, the results (about 30%) stagnate for the total group of B-lineage-ALL (common ALL, pre-B-ALL, pro-B-ALL). Patients with B-lineage-ALL can be subdivided in a high and low risk group according to the presence of risk factors (age, white blood cell count, time to achieve a complete remission, pro-B-ALL and the translocations t[4;11], t[9;22]). The outcome of the subgroup of adult pro-B-ALL has been substantially improved (50%). An increase of treatment results (20%) appears in outlines for patients above 50 years. The Ph/bcr-abl positive ALL has in spite of improved complete remission rates (60-70%) consistently unfavourable survival rates (10%).

Adult↗
PubMed1999

[Acute myeloid leukemia (AML)].

Acute myeloid leukemia (AML) appears related to some environmental factors and higher age. The morphological subtypes reflect genotypes as detected by specific chromosome translocations and related fusion genes. Genotypes determine the disease biology and prognosis. Chemotherapy remains as the backbone of treatment and has brought the long-term disease-free survival to 30-40%. Factors contributing to the improved results are prolonged maintenance, double induction strategy and high dose AraC in postremission and induction phase. Allogeneic bone marrow transplantation adds to the improvements by the graft versus leukemia effect. Autologous stem cell transplantations may allow further escalation of postremission chemotherapy and might thus further improve the cure rate in AML.

Humans↗