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Biomedical subjects

D Hoelzer

Publications and source records attributed to D Hoelzer.

At least 19 recordsLinked to original sources
PubMed1995

Long-term follow-up of adults with acute lymphoblastic leukemia in first remission treated with chemotherapy or bone marrow transplantation. The Acute Lymphoblastic Leukemia Working Committee.

OBJECTIVE: To determine whether the conclusions of a 1991 study, which showed that adults with acute lymphoblastic leukemia in first remission had similar leukemia-free survival rates when treated with chemotherapy or HLA-identical sibling bone marrow transplantation, remain valid after more than 4 years of additional follow-up. DESIGN: Retrospective comparison of two cohorts of patients using left-truncated Cox regression to adjust for differences in baseline characteristics and time to treatment. SETTING AND PATIENTS: Chemotherapy recipients were 484 consecutive patients with acute lymphoblastic leukemia in first remission treated in 44 hospitals in Germany that were participating in two consecutive trials of the German Acute Lymphoblastic Leukemia Therapy Trials Group. Transplant recipients were 234 consecutive recipients of HLA-identical sibling bone marrow transplants for acute lymphoblastic leukemia in first remission in 98 centers, worldwide, reporting data to the International Bone Marrow Transplant Registry. INTERVENTIONS: Intensive combination chemotherapy or HLA-identical sibling bone marrow transplantation preceded by high-dose chemotherapy with or without total body irradiation. MEASUREMENTS: Relapse, treatment-related mortality, and leukemia-free survival rate 9 years after first complete remission. RESULTS: The conclusions of our previous analyses were confirmed. Actuarial relapse probabilities at 9 years were 66% (95% CI, 61% to 70%) for chemotherapy and 30% (CI, 22% to 37%) for transplantation (P < 0.0001). The leukemia-free survival rates at 9 years were 32% (CI, 27% to 37%) for chemotherapy and 34% (CI, 28% to 40%) for transplantation (P > 0.02). CONCLUSIONS: Fewer relapses but more treatment-related deaths were seen with transplantation than with chemotherapy. Thus, leukemia-free survival rates were similar in adults receiving transplantation and adults receiving chemotherapy for acute lymphoblastic leukemia in first remission.

Antineoplastic Agents↗
PubMed1995

Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: a randomized phase III trial.

This prospective multicenter study examined whether simultaneous administration of granulocyte colony-stimulating factor (G-CSF; Filgrastim) and induction chemotherapy for adult acute lymphoblastic leukemia (ALL) could prevent treatment-related neutropenia, infections, and resulting treatment delays. Seventy-six patients were randomly assigned to receive either G-CSF (n = 37) or no growth factor (n = 39) in conjunction with a uniform chemotherapy consisting of cyclophosphamide, cytarabine, mercaptopurine, intrathecal methotrexate, and cranial irradiation. The median duration of neutropenia (absolute neutrophil count < 1 x 10(9)/L) during chemotherapy was 8 days in patients receiving C-CSF, compared with 12.5 days in the control group (P < .002). A similar reduction from 11.5 to 7 days was observed in patients with T-ALL receiving additional mediastinal irradiation (P = .13). Infections occurred in 43% and 56% of patients in the G-CSF and control arm, respectively (P = .25); the incidence of nonviral infections was reduced by 50%, from 32 episodes in the control arm to 16 episodes in the G-CSF arm. Prolonged interruptions of chemotherapy administration were less frequent, with delays of 2 weeks or more occurring in only 24% of patients receiving G-CSF as opposed to 46% in the control arm (P = .01). Accordingly, chemotherapy was completed significantly earlier with the use of G-CSF (39 v 44 days, P = .008). With a median follow-up of 20 months, the probability of disease-free survival was 0.45 in the G-CSF group and 0.43 in the control group (P = .34). In conclusion, adult ALL patients appear to benefit by the simultaneous administration of G-CSF with induction chemotherapy because of a significant reduction in the duration of neutropenia, a trend to fewer infections, and a more rapid completion of chemotherapy.

Adolescent↗
PubMed1995

[Current aspects of therapy in chronic and acute leukemias].

A significant fraction of patients with chronic myelogenous leukemia (CML) in the chronic phase have durable hematologic remissions following treatment with interferon-alpha. Some clinical trials are beginning to show a modest overall survival advantage with interferon compared to hydroxyurea. The only curative therapy for CML is allogeneic bone marrow transplantation. In chronic lymphocytic leukemia (CLL), stable early stage disease requires no treatment. Recent trials have confirmed that several new purine analogues are effective in CLL. In acute myeloid leukemias there appears to be a dose-dependent effect on remission and intensified treatment may increase the percentage of disease free survivors. Hemopoietic growth factors may reduce treatment-related morbidity and mortality. Enhancement of cytotoxicity by prestimulation with GM-CSF is still controversial. All-trans retinoic acid induces remissions in 80% of patients with acute promyelocytic leukemia by forcing the leukemic promyelocytes to maturation. Allogeneic bone marrow transplantation is effective in high risk patients with Philadelphia chromosome positive acute lymphocytic leukemia (ALL), in patients with relapse or resistant acute myelogenous leukemia (AML) or ALL. In patients with ALL a risk-adapted therapy including allogeneic and autologous bone marrow transplantation and the use of hemopoietic growth factors to improve supportive therapy may result in more cures.

Acute Disease↗
PubMed1995

dic(9;20): a new recurrent chromosome abnormality in adult acute lymphoblastic leukemia.

Loss of chromosome 20 and rearrangement of the short arm of chromosome 9 were identified by banding analysis of three adult patients with acute lymphoblastic leukemia (ALL). The G-banding pattern suggested an identical deletion of 9p, but, also, an unbalanced translocation with chromosome 20 was taken into consideration. Dual-color chromosome painting with probes for chromosomes 9 and 20 revealed the presence of material from chromosome 20 at the short arm of the abnormal chromosome 9 in all three cases. Centromeric alpha-satellite DNA of both chromosome 9 and chromosome 20 was demonstrated by fluorescence in situ hybridization and indicated the presence of a dicentric chromosome. The hybridization of a YAC clone of the short arm of chromosome 20 proved that the dicentric chromosome contained the short arm of chromosome 20, which had been suspected from the G-banding pattern. Thus, the rearrangement was interpreted as dic(9;20)(p11;q11.?1). Because this was the sole chromosome abnormality in two patients, dic(9;20) may be a primary chromosome aberration in ALL. In one case, a 9q+ chromosome derived from a Philadelphia (Ph) translocation was involved in the formation of the dicentric chromosome. Immunophenotyping revealed CD10+ B-cell precursor ALL in all three cases. Whereas the two patients in whom dic(9;20) was the sole cytogenetically detectable change are in continuous complete remission for 10 and 45 months, respectively, the Ph+ patient relapsed with leukemia and died 8 months after diagnosis.

Adult↗
PubMed1995

Lactate dehydrogenase-release assay: a reliable, nonradioactive technique for analysis of cytotoxic lymphocyte-mediated lytic activity against blasts from acute myelocytic leukemia.

Treatment of patients in remission of acute myelocytic leukemia using immunotherapy with interleukin 2 is a new approach to prolonging remission duration in this disease. As an important mechanism for the pathophysiology of eradication of residual myelocytic blast populations, activation of cytotoxic effector lymphocytes has frequently been discussed. However, the associated immunological research has been complicated to some extent, because in conventional chromium 51-release assays, blast cells frequently fail to incorporate sufficient amounts of 51Cr and/or spontaneously release high amounts of 51Cr. Recently, we established a culture system which promotes the outgrowth of cytotoxic T lymphocytes in bone marrow-derived mononuclear cells cultured in IL-2. To study cytotoxicity and the responsible mechanisms of the obtained T-cell lines and clones, we modified a previously described cytotoxicity assay, based on the release of lactate dehydrogenase (LDH-release assay) for use in cryopreserved blasts obtained from the bone marrow of patients with acute myelocytic leukemia. Using this assay, we were able to detect cytotoxicity of IL-2-activated peripheral blood lymphocytes from three healthy controls against a number of blast samples obtained from the bone marrow of patients with AML (up to more than 40% lysis at an effector target cell ratio of 20:1). However, a minority of AML blasts seem to be resistant to lysis by IL-2-activated lymphocytes. In bone marrow-derived T-cell lines from patients with AML we detected lytic activity against autologous blasts in three of seven cases tested by LDH release, ranging from 29 to 63% at an effector target ratio of 10:1. Additionally, T-cell clones with different phenotypes were established which were able to mediate cytotoxicity against autologous blast cells. Thus, cytotoxicity against freshly isolated blasts from patients with acute myelocytic leukemia can be analyzed reliably, reproducibly, and without the use of isotopes by the LDH-release assay.

Blast Crisis↗
PubMed1995

Modified antisense oligodeoxynucleotides against the splice acceptor site of tat do not inhibit in vitro hematopoietic colony growth in HIV-positive patients.

The hematopoietic failure in the majority of patients with progressive HIV infection is further aggravated by virustatic agents like azidothymidine. As an alternative therapeutic attempt, three derivatives of an antisense oligodeoxynucleotide (ODN) against the splice acceptor site of the tat gene have been shown to inhibit HIV replication in vitro. This study was aimed at examining whether these agents are toxic to the hematopoietic progenitor cells. To this end, bone marrow cells from HIV-positive and healthy persons were depleted from adherent cells to eliminate fibroblasts. In further experiments, the cells were additionally enriched for CD34-positive hematopoietic progenitor cells or were depleted from delta TCS-1-positive T lymphocytes. At concentrations of 1.25-10 microM, the three antisense ODN did not inhibit any erythrocyte or granulocyte-monocyte colony growth from CD34-positive cells, either from the HIV-positive or from the HIV-negative cohort. In contrast to azidothymidine, which served as inhibitory control, a significant increase of colony growth was seen after depletion of fibroblasts, of delta TCS-1-positive cells, or without cell separation. In conclusion, the three oligodeoxynucleotides do not exert any hematotoxic effect but do increase colony formation from low-density bone marrow cells in vitro and could therefore be useful in future clinical studies.

Antigens, CD↗
PubMed1995

Twenty-three cases of acute lymphoblastic leukemia with translocation t(4;11)(q21;q23): the implication of additional chromosomal aberrations.

The translocation t(4;11)(q21;q23) is one of the most common specific chromosomal aberrations in acute lymphoblastic leukemia (ALL), occurring in 2% of childhood and in 5-6% of adult cases. Especially in adults, the t(4;11) is associated with a poor prognosis. In order to determine the significance of clonal chromosome aberrations that occur in addition to t(4;11), we studied the karyotypes and clinical courses of 23 patients with acute lymphoblastic leukemia and a translocation t(4;11)(q21;q23). Additional clonal chromosome aberrations were found in ten patients. An isochromosome i(7)(q10) and a trisomy 6 were observed most frequently as secondary anomalies. Clonal evolution was detected in four of six patients analyzed at diagnosis as well as at relapse. With treatment carried out according to modern risk-adapted therapy protocols, no difference in outcome was observed between patients with clonal chromosome aberrations in addition to t(4;11) at diagnosis and those without.

Adolescent↗
PubMed1995

High-dose cytosine arabinoside and daunorubicin postremission therapy in adults with de novo acute myeloid leukemia. Long-term follow-up of a prospective multicenter trial.

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

Adolescent↗
PubMed1995

Bone marrow-derived T-cell clones obtained from untreated acute myelocytic leukemia exhibit blast directed autologous cytotoxicity.

The eradication of minimal residual blast populations by activation of autologous cytotoxic cells with interleukin 2 (IL-2) is a new promising tool in the treatment of acute myelocytic leukemia (AML). However, the immunological effector cells are not yet clearly defined. The present study was designed to investigate the presence of cytotoxic precursor cells in active AML and to identify phenotypical and functional characteristics of autologous anti-leukemic cytotoxic effector cells. For this purpose, mononuclear cells (MNC) containing at least 70% leukemic blasts were isolated from bone marrow of untreated AML and cultured in the presence of 3000 IU/ml recombinant IL-2 (rIL-2) for 6-8 weeks. Under these conditions, T-cells were selected in the bone marrow cultures and overgrew the leukemic blasts. The resulting T-cell populations were cloned by limiting dilution and the clones obtained were characterized for their phenotypical and functional patterns. Totally, cloning resulted in 68 clones and a few cell lines. The clonality was verified by RT PCR analysis of TCR V beta gene expression. All clones obtained stained positive for CD2, CD3, DR and CD56. The vast majority (68%) of T-cell clones/lines was CD4+, a few clones expressed CD8 (19%) or CD4 and CD8, and four clones were of TCR gamma delta origin. Seven of 15 clones tested, including three CD4+, two CD8+ and two TCR gamma delta(+)-clones were found to be cytotoxic against autologous leukemic blast cells. All except one clone expressed oncolytic activities against allogeneic blasts too. One of the TCR gamma delta(+)-clones demonstrated NK activity by lysis of K562 targets. The majority of the T-cell-clones released IL-2, IL-8, TNF-alpha, GM-CSF but only a few IFN gamma and expressed high levels of mRNA for IL-2, TGF-beta and IL-10. None of the clones was found to produce IL-3, IL-4, IL-7 and TNF-beta. The data provide evidence of the existence of T-cell precursors in untreated AML bone marrow differentiating to cytotoxic cells with activity against autologous and allogeneic AML blast cells.

Bone Marrow Cells↗
PubMed1995

AML blasts variably express interleukin 2 receptor alpha, beta or gamma chains without measurable effects on proliferation, cytokine message expression or surface expression of adhesion molecules upon stimulation with interleukin 2.

Preliminary clinical studies including interleukin 2 (IL-2) in chemotherapy strategies for treatment of acute myeloblastic leukemia (AML) suggest that IL-2 may improve the disease-free survival of the patients. Because of reports showing interleukin 2 receptor expression on AML blasts, it is important to know whether IL-2 may directly influence these leukemic cells. In initial studies using flow cytometry to analyze surface expression of interleukin 2 receptors (IL-2R), we found expression of the IL-2R alpha chain on blast cells in 26% and of the IL-2R beta-chain in 81% of the patients. To confirm these results at the transcriptional level, we studied the expression of RNA of the IL-2R alpha, beta, and gamma chains by RT-PCR in the bone marrow of 38 newly diagnosed patients with AML and in three AML-derived cell lines. RNA of the alpha chain was detectable in 11/38 patients, the beta chain in 10/38 patients and the gamma chain in 30/38 patients with AML. Blast cells obtained from colonies growing in semisolid media expressed mRNA for IL-2R. RNA for all three IL-2R chains was expressed in lines KG1, HEL 92.1.7 and K562. In comparison with unstimulated cell lines, incubation of the three lines with various amounts of IL-2 over 3 and 14 days did not increase their growth or change message expression of IL-2R, IL-10, and TGF-beta and surface expression of the adhesion molecules CD 11, CD 18, CD 29 and CD 54. In conclusion, despite expression of IL-2 receptors, AML blasts do not respond to IL-2 by proliferation, message expression for various cytokine genes and surface expression of cellular adhesion molecules.

Base Sequence↗
PubMed1995

Changes in erythroid progenitor cell and accessory cell compartments in patients with myelodysplastic syndromes during treatment with all-trans retinoic acid and haemopoietic growth factors.

Differentiation induction therapy is used in myelodysplastic syndromes (MDS) to improve maturation defects and to restore impaired function of malignant cells. To this end, 18 patients with MDS received either a combination therapy consisting in study 1 of all-trans retinoic acid (ATRA) and granulocyte-colony stimulating factor (G-CSF), or in study 2 of a combination with ATRA, G-CSF, erythropoietin (Epo) and tocopherol. The ANC increased in 19/20 patients in both studies, whereas an increase in haemoglobin concentration, platelet counts or reduction of transfusion requirement was seen in only 8/20 patients, correlating strongly with good BFU-E growth (P < 0.001). To assess the role of accessory cells in the modulation of the haemopoietic response to treatment, we analysed the capacity of peripheral blood monocytes to secrete cytokines (IL-1 beta, IL-6, IL-8, TNF alpha). Secretion of all cytokines was significantly reduced before therapy when compared with healthy controls, but increased during therapy, reaching normal levels for IL-8. These data indicate that a combination therapy with ATRA and cytokines improves impaired cytokine secretion from monocytes and induces a multilineage clinical response in a subgroup of MDS patients characterized by an almost intact erythroid compartment. In contrast, induction of TNF alpha might be responsible for treatment failure.

Adult↗
PubMed1995

Interleukin-2 bolus infusion as late consolidation therapy in 2nd remission of acute myeloblastic leukemia.

The activation of autologous cytotoxic cells by interleukin-2 (IL-2) may be a promising tool for elimination of minimal residual blast populations in patients with acute myelocytic leukemia (AML) to prolong disease-free survival. Here, we report the results of a phase II study using IL-2 for consolidation therapy in patients with second remission of de novo AML. All patients in 1st relapse of AML received a uniform induction therapy consisting of intermediate high-dose AraC (iHDAraC) 2 x 600 mg/m2 d1-4 and VP-16 100 mg/m2 d1-7. Patients achieving 2nd remission were treated with 4 cycles recombinant IL-2 (rIL-2) 9 x 10(6) IU/m2 administered on d1-5 and 8-12/cycle as 1h infusion every six weeks. In 37/66 (56%) evaluable patients, complete remission (CR) was achieved. So far, 21/37 patients (4 after additional autologous bone marrow transplantation (ABMT) received rIL-2 consolidation. Three patients are too early for evaluation, 4 received allogeneic BMT, 6 relapsed before IL-2 was scheduled and 4 refused treatment with rIL-2. The median disease-free survival (DFS) was 11 (4-49+) months. Up to now, in 5/21 (24%) patients the duration of 2nd remission exceeded that of 1st remission 7/21 (33%) are in ongoing 2nd remission (7+ to 49+ months). The side effects of rIL-2 were generally moderate and manageable. Only in two patients, previously treated with ABMT, severe side effects occurred; septicaemia and pneumonia in one patient and desquamative erythrodermia in the second one. In accordance with other studies rebound lymphocytosis with a marked increase of CD56(+)-cells and release of secondary cytokines such as TNF-alpha, IFN-gamma and IL-6 was observed. The schedule is feasible and the data suggest a possible benefit for DFS, which, however has to be confirmed by randomized trials.

Adult↗
PubMed1995

GM-CSF in a double-blind randomized, placebo controlled trial in therapy of adult patients with de novo acute myeloid leukemia (AML).

We investigated whether GM-CSF given concomitantly with chemotherapy (CT) and thereafter, improves the outcome of adults with de novo AML by increasing the efficacy of CT and reducing infections. CT included Ara-C, daunorubicin and etoposide (DAV) for induction and early consolidation therapy and one cycle with high-dose (patients aged < or = 50 years) or intermediate dose Ara-C (patients aged > 50 years)/daunorubicin for late consolidation therapy. Eight patients were randomized after DAVI to receive either GM-CSF (E. coli, 250 micrograms/m2/day, s.c.) or placebo starting 48 h prior to DAVII and the subsequent courses and given throughout CT until the absolute neutrophil count had recovered to > 500/microliters. The CR rate was 81% in the GM-CSF and 79% in the placebo group (p = 0.57; Fisher's exact test). The probability of relapse-free survival at 41 months after a median follow-up of 35 months was 42% in the GM-CSF and 41% in the placebo group (p = 0.89; log rank test). GM-CSF did not shorten the period of neutropenia < or = 500/microliters, while it prolonged the duration of thrombocytopenia < or = 25,000/microliters. The incidence and severity of infections as well as the non-hematological toxicity were similar in both groups. In summary, in this randomized trial GM-CSF as an adjunct to AML therapy was feasible. For the present GM-CSF does not have a significant effect on treatment outcome.

Adolescent↗
PubMed1994

A low affinity chimeric human alpha/beta-granulocyte-macrophage colony-stimulating factor receptor induces ligand-dependent proliferation in a murine cell line.

The high affinity receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF) is composed of at least two subunits, an 85-kDa low affinity GM-CSF-binding protein (alpha-GMR) and a 120-kDa beta-subunit (beta-GMR) necessary for high affinity binding and signal transduction. Previous studies have shown that deletion of the intracellular domain of alpha-GMR inactivates the receptor's ability to support proliferation, but has no effect on GM-CSF binding. Using anti-alpha-GMR- and anti-beta-GMR-specific antibodies, we show that alpha-GMR and beta-GMR coprecipitate only after GM-CSF binding, suggesting that binding of GM-CSF induces stabilization or assembly of an activated receptor complex involving recruitment of beta-GMR chains. To understand the contribution of each subunit of this receptor to the generation of an activated receptor complex, we attempted to construct minimal receptors with some or all of the functions of the wild-type heterodimer. We found that a hybrid human alpha/beta-GMR molecule in which the extracellular and transmembrane segments are composed of alpha-GMR sequences and the intracellular segment is composed of beta-GMR bound GM-CSF with low affinity, but activated tyrosine kinase activity, induced receptor internalization, and supported short- and long-term proliferation of transfected Ba/F3 cells. At least 1 ng/ml human GM-CSF was required for growth stimulation, and maximal proliferation occurred at a concentration of 10 ng/ml. This was 10-100-fold more than needed to stimulate growth of Ba/F3 cells expressing both full-length human alpha-GMR and beta-GMR and 1000-fold less than needed to stimulate growth of Ba/F3 cells expressing only human alpha-GMR. These results indicate that the cytoplasmic domain of alpha-GMR is not required to initiate a unique signaling event for proliferation in Ba/F3 cells, but can be functionally replaced by the cytoplasmic domain of beta-GMR.

3T3 Cells↗