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G Heil

Publications and source records attributed to G Heil.

At least 55 records · Page 3Linked to original sources

Chronic myelogenous leukemia in blast crisis: retrospective analysis of prognostic factors in 90 patients.

Ninety patients with Philadelphia chromosome-positive chronic myelogenous leukemia in blast crisis were reviewed to identify significant prognostic associations. At diagnosis of blast crisis the main clinical, laboratory, and cytogenetic data were recorded and evaluated for prognostic significance. At the time of the analysis 89 patients had died, with a median survival of 11 weeks from diagnosis of blast crisis. Patient characteristics demonstrated in the univariate analysis to have significant association with shorter survival were: thrombocythemia, leukocyte count above 20 x 10(9), Karnofsky index < 50%, nonlymphoid blast cell morphology, cytogenetic clonal evolution, the presence of a double Philadelphia chromosome or trisomy 8, and no response to therapy. In 17 of 59 patients (29%) evaluable for response to therapy a complete or partial remission was achieved. These responders had a significantly longer median survival (25 weeks) as compared with nonresponders (9 weeks). Response to therapy was significantly better in lymphoid blast crisis and in patients without clonal evolution. In a multivariate analysis containing all significant variables of the univariate analysis two parameters retained their prognostic significance: response to therapy and trisomy 8. In spite of the short overall survival in blast crisis, the determination of prognostic factors may be a useful tool for the clinician planning therapy, especially new therapeutic approaches.

Adult↗

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↗

Establishment and characterization of a novel CD34-positive human myeloid leukemia cell line: MHH225 growing in serum-free culture.

A new human multilineage myeloid leukemia cell line, MHH225, has been established in our laboratory from the bone marrow of a 60-year-old patient suffering from acute megakaryoblastic leukemia (M7); it provides a unique model for studying the effect of biologic and chemical agents on the lineage specificity of a multipotent myeloid leukemia clone containing a mixed population of megakaryoblast, erythroblast, and myeloblast cells in a serum-free culture. Morphologically, all 225 cells are large blast cells with basophilic cytoplasm containing no granules, large round nucleus containing 2-3 prominent nucleoli, and fine chromatin structure and a large nuclear/cytoplasm ratio. The MHH225 cells are CD34+HLA-DR+CD33+CD13+ with 57.6%, 28.3%, and 7.8% of them being CD41+, glycophorin A+, and CD15+, respectively, and all lymphoid-specific antigens are negative. The karyotype analysis of MHH225 cells revealed a deletion of the short arm of chromosome 7: del(7)(p13)-, a whole-arm translocation between the long arms of chromosomes 9 and 21: t(9;21)(q10;q10), and a chromosome 11 with an elongated long arm due to duplication of chromosome 11 material as well as to translocation of part of chromosome 9 onto 11q+. Also, chromosome 21 was deleted in some metaphases or showed a ring formation in other metaphases. Utrastructurally, MHH25 cells display a strong platelet peroxidase activity in the nuclear envelope and the endoplasmic reticulum. The MHH25 cells have been grown exponentially without growth factors or conditioned media or serum only in RPMI1640 culture medium. None of the myelopoietic growth factors, i.e., interleukin-3, GM-CSF, G-CSF, erythropoietin, or interleukin-6, has any effect on the proliferation and differentiation of MHH25 cells. The two, hematopoietic inhibitory cytokines, interferon-alpha and tumor necrosis factor-alpha, have only minimal growth inhibitory effect. Stem cell factor showed only weak growth-stimulatory effect on MHH225 cells but significantly inhibited chemotherapy-induced apoptosis in these cells. The new cell line MHH225 should constitute a useful model for studying stem cell antigen (CD34)-positive human multilineage myeloid leukemia cells carrying a deletion in the short arm of chromosome 7 and an aberration in chromosome 11 and provide a unique tool for investigating human hematopoietic stem cell biology and its cytokine regulation in serum-free cultures. To our knowledge, the MHH225 cell line is the first human CD34-positive leukemia cell line growing in serum-free cultures to be established.

Antigens, CD34↗

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↗

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↗

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↗

Acute lymphoblastic leukemia in patients over 59 years of age. Experience in a single center over a 10-year period.

We report data of 29 consecutive patients aged 60 years or older with newly diagnosed acute lymphoblastic leukemia (ALL) treated at a single center between 1983 and 1992. Immunophenotyping was performed in 26 patients. According to the immunological classification used at the time of diagnosis, 14 had common-ALL, two had T-ALL, six had null-ALL, three had myeloid antigen-positive ALL with both lymphoid and myeloid markers, and one had B-ALL. One patient died before therapy could be instituted. Twenty-four patients received intensive induction chemotherapy. Nine of these patients died during the first 8 weeks, eight due to infections and one due to liver failure after asparaginase. In 14 of the remaining patients treated intensively, scheduled treatment was discontinued prematurely due to treatment-related toxicity and was replaced by milder chemotherapy. Four patients aged 75-77 years were treated with vincristine and prednisone. Only one patient who completed a whole study protocol survived more than 5 years. Twelve of the 28 patients treated with chemotherapy achieved complete remissions. The median survival was 5 months (range 1-103+). Median survival in patients with CR was 9.0 months. Actuarial survival is 3%. Our data demonstrate a poor prognosis in ALL patients over 59 years of age. The reasons were a high mortality during intensive induction therapy due to toxicity of treatment and a short remission duration.

Aged↗

Peroxidase expression in acute unclassified leukemias: ultrastructural studies in combination with immunophenotyping.

The lineage affinity of 61 cases of acute unclassified leukemias (AUL) was reevaluated by ultrastructural analysis of peroxidase expression (POEM) in combination with immunophenotyping. In 24 cases a significant proportion of the blasts displayed ultrastructural myeloperoxidase (UMPO) and in another 3 cases platelet peroxidase (UPPO) suggesting the allocation of these leukemias to the myeloid or megakaryoblastic lineage. No significant correlation between myeloid surface marker expression and POEM positivity could be detected, while the presence of the CD 19 or CD 24 antigen significantly correlated with POEM negativity. The detection of lymphoid markers on POEM+ blasts indicates, that these leukemias might be derived from bipotential progenitors, which have retained their lymphoid antigens during myeloid differentiation. In one case a bilineage leukemia with a POEM+/CD 19- and a POEM-/CD 19+ population could be identified by immunoelectron microscopical studies (IEM). The remaining 34 AUL cases were POEM negative. Combined data suggest that these cases probably derive from early lymphoid progenitors. Taken together, AUL are heterogenous in presentation and in their cellular origin including a major portion of cases with an unequivocal myeloid differentiation detectable by ultrastructural analysis of myeloperoxidase expression.

Acute Disease↗

CD 54 expression and its role in homotypic aggregation of the blasts of acute myeloblastic leukemias (AML).

CD 54 (ICAM-1) expression was studied on blasts of 13 cases of de-novo AML prior to and after stimulation by interferon-gamma (IFN-gamma). Furthermore, its functional activity was studied by analysis of the influence of CD 54 on homologous interaction of the blasts. Prior to culture only a minority of the blasts displayed CD 54 positivity. Timed incubation of the blasts in RPMI-1640/FCS or serum-free medium 'spontaneously' increased the percentage of CD 54 positive cells in 11/13 cases with a main increase after 24 h. IFN-gamma (500 IU/ml) further enhanced CD 54 positivity in 6/11 cases. In 2/13 cases neither a 'spontaneous' nor an IFN-gamma induced CD 54 upregulation occurred. The homotypic aggregation of the AML blasts paralleled ICAM-1 expression in that (1) in all but the two CD 54 negative cases autologous cluster formation could be detected, (2) IFN-gamma enhanced cluster formation in 5/6 cases in which it had enhanced CD 54 upregulation, (3) incubation of the blasts in the presence of an anti-CD 54 MoAb (clone 84H10) reduced the 'spontaneous' and IFN-gamma induced cluster formation in a majority of the cases. Taken together, ICAM-1 expression on AML blasts is heterogenous with respect to (1) its 'constitutional' expression and (2) its 'spontaneous' and IFN-gamma-induced upregulation, while it seems to be functionally active once expressed on the surface membrane. The reason for the heterogenity, which did not correlate with the FAB subtype, and its importance remain unclear.

Adult↗

Simultaneous administration of granulocyte colony-stimulating factor (Filgrastim) and induction chemotherapy in acute lymphoblastic leukemia. A pilot study.

The present study was designed to determine whether Filgrastim, a neutrophil-specific hematopoietic growth factor, could be administered simultaneously with intensive induction chemotherapy for adult acute lymphoblastic leukemia (ALL). The effect of Filgrastim on the severity of chemotherapy-induced neutropenia, fever, and infections was assessed in 15 patients treated according to the protocol of the German multicenter ALL (GMALL) trial 04/89. Filgrastim (5 micrograms/kg/day) was given concurrently with successive cycles of cyclophosphamide, cytosine-arabinoside (ara-C), 6-mercaptopurine (6MP), prednisone (PRD), intrathecal methotrexate, and prophylactic cranial irradiation. During the study period the median total duration of severe neutropenia (< 0.5 x 10(9)/l) in 13 evaluable patients was 8 days, individual periods of neutropenia typically were short. Infections occurred in six patients; seven patients remained fever-free during treatment with Filgrastim. We conclude that simultaneous treatment with Filgrastim and chemotherapy in this specific setting is feasible and well tolerated. The efficacy of this treatment approach in terms of overall treatment results requires further testing in a randomized trial.

Adolescent↗

Aggressive chemotherapy combined with G-CSF and maintenance therapy with interleukin-2 for patients with advanced myelodysplastic syndrome, subacute or secondary acute myeloid leukemia--initial results.

Aggressive chemotherapy of advanced myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) evolving from MDS, subacute AML and secondary AML has usually been associated with low complete remission (CR) rates, a high incidence of early death, and low disease-free survival. We therefore have initiated a phase-III trial of aggressive chemotherapy consisting of idarubicin, cytosine arabinoside, and VP-16 to improve the CR rate. Each chemotherapy cycle is followed by G-CSF to accelerate neutrophil recovery and to reduce the incidence of infections. Until now, 19 patients with high-risk AML have been entered. The CR rate is 47%, with only one death during induction. Patients achieving CR are randomized to receive either high-dose or low-dose interleukin-2 to eliminate residual leukemic cells and to prolong the duration of remission.

Adult↗

A new technical approach for the ultrastructural analysis of hematopoietic cells using cell monolayers adherent to electron-transparent melamine resins.

The melamine resin is a polymer of a hexamethylol melamine ether which can coat glass slides with an electron-transparent foil (approximately 80 nm thick) after polymerization by p-toluene sulphonic acid and warming. Provided that the cells had been resuspended in a serum-free medium, normal peripheral blood, or bone marrow cells, blasts of different acute leukemias, cells of B-cell chronic lymphocytic leukemia, and of the cell-lines K562, KG1a, and HL-60 became adherent to the melamine-resin-covered glass slides. The optimal sedimentation time and cell concentration was 45 min and 10(7) cells/ml, respectively. Moreover, in serum-free culture medium the cells could be maintained adherent for up to 96 h without a great loss in cell number and viability. For transmission electron microscopical (TEM) analysis, the monolayers could be embedded in situ in epon after routine fixation and staining procedures. Alternatively, the foils could be removed from the glass and mounted on grids for whole mount electron microscopic analysis (WMEM). Both methods could be combined with immunogold labelling for the detection of surface antigens. This technique permits ultrastructural in situ analysis of morphological and/or immunological changes of cells induced by in vitro stimulation.

Cell Adhesion↗

Treatment of relapsed or refractory adult acute lymphocytic leukemia.

Sixty-six adult patients were treated for relapsing or refractory acute lymphocytic leukemia (ALL). The induction treatment consisted in a (1) first phase with vindesine 3 mg/m2 intravenously (IV) on days 1, 8, and 15; daunorubicin 45 mg/m2 IV on days 1, 8, and 15; erwinia-asparaginase 10,000 U/m2 IV on days 7, 8, 14, and 15; and prednisone 60 mg/m2 orally on days 1 to 21 and a (2) second phase with cytarabine 3000 mg/m2 as a 3-hour infusion two times a day on days 1 to 4 (in patients greater than 50 years of age we used 1000 mg/m2), and etoposide 100 mg/m2 IV on days 1 to 5. Side effects of induction Phase I were predominantly hematologic with subsequent infections. In Phase II, some patients additionally had gastrointestinal, cutaneous, ocular, and hepatic toxicity. Five patients died during Phase I and another died during Phase II. Five of these patients had T-cell ALL. Thirty-four (64%) of 54 patients in their first relapse had a complete remission (CR) with a median disease-free survival (DFS) of 2.9 months. The median overall survival (OAS) was 6.6 months. Seven of 12 patients with primary refractory disease, a second relapse, or relapse after bone marrow transplantation (BMT) had a CR. The CR rate and survival after first relapse was significantly better in patients with a preceding CR of more than 18 months compared with those with a shorter preceding remission. The leukocyte count was a second significant but not independent risk factor. There was a negative correlation between the leukocyte count and the duration of the preceding CR. The duration of the preceding CR was the major prognostic factor for survival in multivariate analysis. Twenty-two patients received BMT. None of nine patients with autologous BMT is alive and disease-free; 5 of 13 who underwent allogeneic BMT are. It was concluded that this treatment efficiently induced remission with tolerable toxicity. The remission duration should be improved by optimized consolidation treatment.

Adult↗

Human interleukin-7 induces proliferation of neoplastic cells from chronic lymphocytic leukemia and acute leukemias.

The biologic effects of interleukin-7 (IL-7) and the expression of specific IL-7 membrane receptors on isolated neoplastic cells from previously untreated patients with chronic lymphocytic leukemia as well as acute leukemias were investigated in vitro. Leukemic cells were incubated for up to 6 days with various concentrations of IL-7 (0.01 to 2,000 U/mL). Neoplastic cells of the T- or B-phenotype from chronic as well as from acute leukemias proliferated in a dose-dependent manner. Cells from acute myeloid leukemias also proliferated in response to IL-7. An optimal proliferative effect was achieved between 96 and 120 hours with 200 U/mL IL-7. Combinations of IL-7 with IL-2 and tumor necrosis factor-alpha showed an additive effect on [3H]TdR incorporation. IL-7 binding assays gave a value of approximately 33 to 180 high-affinity (kd approximately 20 pmol/L) binding sites/cell and approximately 241 to 3,280 low-affinity (kd approximately 600 pmol/L) binding sites/cell. Receptor expression correlated with the proliferation in response to IL-7. These data indicate that IL-7 can induce proliferation of relatively mature tumor cells, and that this effect is not restricted to the lymphoid lineage.

Adult↗

Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission.

OBJECTIVE: To compare efficacy of intensive postremission chemotherapy with allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia (ALL) in first remission. DESIGN: Retrospective comparison of two cohorts of patients. SETTING: Chemotherapy recipients were treated in 44 hospitals in West Germany in two cooperative group trials; transplants were done in 98 hospitals worldwide. PATIENTS: Patients (484) receiving intensive postremission chemotherapy and 251 recipients of HLA-identical sibling bone marrow transplants for ALL in first remission. Patients ranged from 15 to 45 years of age and were treated between 1980 and 1987. MAIN RESULTS: Similar prognostic factors predicted treatment failure (non-T-cell phenotype, high leukocyte count at diagnosis, and 8 or more weeks to achieve first remission) of both therapies. After statistical adjustments were made for differences in disease characteristics and time-to-treatment, survival was similar in the chemotherapy and transplant cohorts: Five-year leukemia-free survival probability was 38% (95% CI, 33% to 43%) with chemotherapy and 44% (CI, 37% to 52%) with transplant. No specific prognostic group had a significantly better outcome with one treatment compared with the other (6% for the difference; CI, -3% to 15%). Causes of treatment failure differed: With chemotherapy, 268 (96%) failures were from relapse and 11 (4%) were treatment-related; with transplants, 43 (32%) failures were from relapse and 92 (68%) were treatment-related. CONCLUSIONS: These results suggest that bone marrow transplants currently offer no special advantage over chemotherapy for adults with acute lymphoblastic leukemia in first remission.

Adolescent↗