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PubMed1999

Evidence for the involvement of the glutathione pathway in drug resistance in AML.

We have studied altered drug detoxification through the glutathione pathway as a possible mechanism of resistance in 38 patients with AML. GST alpha, mu and pi expressions were determined using immunocytochemistry, the median percentages of positive cells being 73% (range 0-98), 55% (range 0-99) and 97% (range 80-100) respectively. MRP expression was measured using MRPm6 MoAb and flow cytometry. Results were expressed as the ratio of fluorescence associated with MRP over that of an isotype matched control (median, 1.32; range 0.95-2.15). Statistical analyses showed a significant increase in GST alpha expression in blast cells showing in vitro resistance to doxorubicin, with a median value of 78% positive cells compared to 41% in the sensitive group (p < 0.02). There was a significant reduction, however, in GST mu expression from a median value of 60% in newly presenting patients to 40% in a group of patients who had received previous cytotoxic therapy (p < 0.02). Interestingly, patients with high GST mu expression appeared to co-express MRP (p < 0.05). In vitro drug modulation studies, comparing the cytotoxic effect of doxorubicin +/- ethacrynic acid at 6.5 microM resulted in only one significant increase in sensitivity (2.6-fold), out of 22 comparisons. These results support the theory that altered detoxification through the glutathione pathway contributes towards drug resistance in AML. Further studies using fresh blast cells are required to elucidate the importance of this mechanism for individual patients.

ATP-Binding Cassette Transporters↗

PubMed1999

Comparison of P-glycoprotein expression and function with in vitro sensitivity to anthracyclines in AML.

The importance of P-glycoprotein (P-gp) in AML has been well documented. Resistance to the anthracyclines can be overcome by several agents including Cyclosporin A (CsA), PSC833 and GF120918. We describe an investigation into the expression, using MRK16 and UIC2, and function of P-gp using daunorubicin with and without modulators by flow cytometric analysis on previously frozen blast cells from 27 patients with primary or secondary AML. We compared this with the in vitro chemosensitivity, using the MTT assay, of fresh blast cells from the same patients. Whilst we found a correlation between P-gp function using CsA and GF120918 and expression using MRK16 (p < 0.05) and (p < 0.02) respectively, we were unable to find any overall correlation between expression and function of P-gp with either in vitro sensitivity to the anthracyclines, previous treatment, or 1 degree or 2 degrees disease. However it was possible to identify individual patients whose cells exhibited P-gp expression and function teamed with in vitro resistance to, and modification of, the anthracyclines. Furthermore, it is possible to identify which modulator had the greatest effect. The fact that we obtained higher indications of resistance reversal using the MTT assay along with finding P-gp expression and function in patients sensitive to the anthracyclines, suggests studies of P-gp should be teemed with chemosensitivity testing to identify specific patients who will benefit.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1987

Improved treatment results in childhood acute nonlymphoblastic leukemia with the BFM-AML protocol 78 in a multicenter study in the GDR.

Eighty-seven children with acute nonlymphoblastic leukemia were treated with the AML protocol BFM 78 between June 1979 and February 1986 in a multicenter study in the GDR. Seventeen children (20%) died from early complications, eight did not respond to therapy. Fifty-eight patients (70%) achieved a complete remission. Twenty-three patients relapsed. The life table analysis revealed after 5 years a probability for event-free survival of 36% (SD = 6%) and an event-free interval of 51% (SD = 8%). Six patients were transplanted in first remission. Two of them died; one (M 1) on day + 19 from encephalopathy and one (M 4) on day + 60 from acute GVHD. The overall results are in good correlation with the original BFM study, but there are differences in the subtypes. Results are superior to other AML protocols in our group.

Actuarial Analysis↗

PubMed1980

The use of the AML scale with a headstart population: normative and validation studies.

The use of the AML with 584 4-year-old children in a Headstart program was investigated. The AML was found to be a reliable and valid instrument to use as a means of identifying emotional and learning problems. Normative data in this study were very similar to that previously found for kindergartners. Sex differences were found on almost all items requiring separate analyses for males and females. The A scale and total score contributed most to the identification of emotional disturbance in females. For males, however, the M scale and total score were most helpful. Mentally retarded males and the learning-disabled children could best be identified using the L scale. The use of a 90th centile cutoff method was found to be an easy and accurate means of identification.

Child, Preschool↗

PubMed1983

Immunotherapy in the treatment of acute myelogenous leukemia (AML): rationale, results and future prospects.

Patients with AML in complete remission (CR) are immunosuppressed; remission lymphocytes of at least a part of the patients are able to recognize autologous leukemic blasts; the CR represents a minimal residual disease. Thus, important conditions for a potentially successful active immunotherapy are given. Results of most earlier randomized trials on immunotherapy revealed some, but limited benefit with respect to survival. Encouraging effects, however, have been achieved by immunizing CR patients with high-dose neuraminidase-treated allogeneic blasts. Because these data have not been confirmed until now we recently initiated a randomized study utilizing identical treatment protocols. The preliminary results of the ongoing study still do not allow to draw any firm conclusions. Specific monoclonal antibodies or autologous cytotoxic T-cells may be useful tools for future immunotherapy of AML.

Animals↗

PubMed1995

AML-MO: clinical entity or waste basket for immature blastic leukemias? A description of 14 patients. Dutch Slide Review Committee of Leukemias in Adults.

In the period from August 1991 to August 1994, the Dutch Slide Review Committee of Adult Leukemias classified 14 leukemias as AML-M0. We reviewed the clinical characteristics and response to therapy of these patients. Eight patients were male. Patients' age ranged from 7 to 77 years (medium age 62 years). There was a striking homogeneity in morphological appearance of the blasts, being small to medium-sized round cells with often an eccentric nucleus with fine chromatin, several distinct nucleoli, and a high nucleo-cytoplasmic ratio. In addition to myeloid-associated markers such as CD13 and CD33, the blasts of all patients were positive for CD34 and HLA-DR, pointing to their immature differentiation stage. TdT was present in the blasts of 71%, CD7 was positive in the blasts of 42% of the patients. No consistent cytogenetic abnormalities were found. With respect to the treatment outcome, four patients achieved a complete remission after remission-induction treatment. The median survival was 4.5 months. Our present study shows AML-M0 to be an immature leukemia, uniform in morphology and immunological phenotype, with no consistent cytogenetic phenotype and with a poor clinical outcome.

Acute Disease↗

PubMed1993

The appearance of reticulocytes with medium or high RNA content is a sensitive indicator of beginning granulocyte recovery after aplasiogenic cytostatic drug therapy in patients with AML.

Flow-cytometric reticulocyte counts including their maturation status were performed during follow-up of induction (n = 5) and consolidation (n = 7) polychemotherapy in nine patients with acute myeloid leukemia (AML) using a Sysmex R-3000 automated counter. The reticulocytes fell to an extreme nadir (< 0.01/pl)--as did leukocytes and platelets--and consisted of cells with low fluorescence ratio (LFR) only. After a median interval of 16 days, the fraction with medium fluorescence ratio (MFR) began to rise, preceding the reticulocytes with high fluorescence ratio (HFR) for a median of 1 day in all cases with partial (n = 1) or complete (n = 8) remission. At a median of 7 days after MFR and 5 days after HFR the granulocytes reached the critical limit of > or = 0.5/nl. The reticulocytes rose to the normal range after 9 and 7 days, respectively. Automated flow-cytometric reticulocyte counting including the maturation status has been shown to provide an accessible measure of erythroid activity, which may be of predictive value for granulocyte recovery after aplasiogenic polychemotherapy in AML patients.

Acute Disease↗

PubMed1991

Hepatic and splenic abscesses--a common complication of intensive chemotherapy of acute myeloid leukemia (AML). A prospective study.

In order to determine the frequency of hepatosplenic abscesses in AML patients during chemotherapy and to evaluate the clinical and laboratory characteristics of this complication we performed a prospective study over a 28-month period. Fifty-five consecutive patients with de novo AML or relapse who received intensive chemotherapy underwent regular ultrasound examinations. In 16 patients (29.1%) hepatic and/or splenic abscesses were detected sonographically. Histopathological evidence for abscess formation was obtained in five of these 16 patients. In three patients granulation tissue and in one patient necrotizing granulomas were found. Causative micro-organisms were proven in only three patients: Candida hyphae were demonstrated in one patient, gram-positive cocci in another. Bacteria and fungi were seen in the tissue specimen of the third patient. Patients with hepatosplenic abscesses had significantly prolonged fever after neutrophil recovery but did not differ from patients without abscesses in any other laboratory or clinical features. Due to the absence of specific alerting clinical and laboratory signs and symptoms of hepatosplenic abscesses, routine ultrasound examination is required for detection of this complication. The presence of hepatic and/or splenic abscesses does not necessarily worsen the prognosis, but it may influence the decision on further chemotherapy and antimicrobial treatment.

Abscess↗

PubMed1990

Treatment strategies in acute myeloid leukemia (AML). A. First-line chemotherapy.

Chemotherapy remains the backbone of treatment in AML. Of all adult patients 65% go into remission and have a chance of longer survival and of even being cured. Among the responders, 25% can be cured by intensive and long-term chemotherapy. Since the effect of chemotherapy appears not to be limited to a special period of time, its antileukemic and curative potential could be further exploited by multiple-step chemotherapy combining double induction, intensified consolidation and long-term maintenance. Improved antimicrobial treatment and the use of hematopoietic growth factors may help making multiple-step chemotherapy practicable, thereby increasing the cure rate in AML.

Acute Disease↗

PubMed2003

Monitoring minimal residual disease in AML: the right time for real time.

Detection of minimal residual disease (MRD) by polymerase chain reaction (PCR) has become an essential tool for molecular monitoring of acute myeloid leukemia (AML). Currently, specific translocation markers are available for 40-50% of AMLs. Expression markers may widen this spectrum to 70-90%. Quantitative PCR (Q-PCR, real-time PCR) is now as sensitive as conventional two-step PCR and could improve as well as facilitate clinical decision-making. Q-PCR has been applied to a variety of molecular markers, delineating threshold levels early after induction therapy, for postinduction monitoring, as well as for the detection of relapse. For most markers, lack of decline of transcript levels by less than 2 logs after chemotherapy has been established as a poor prognostic sign. Moreover, increases in transcript levels are almost invariably associated with relapse. However, the predictive value of PCR negativity after chemotherapy is not as clear. The major tasks for the future will be standardization of Q-PCR techniques, exact definition of threshold levels, and monitoring schedules in bone marrow (BM) and peripheral blood (PB), as well as investigation of novel markers found by microarray analysis.

Gene Duplication↗

PubMed2000

Intensive chemotherapy with idarubicin, ara-C, etoposide, and m-AMSA followed by immunotherapy with interleukin-2 for myelodysplastic syndromes and high-risk Acute Myeloid Leukemia (AML).

Intensive chemotherapy followed by treatment with interleukin-2 (IL-2) was evaluated in a prospective, randomized, multicenter trial including 18 patients with refractory anemia with excess of blasts in transformation (RAEB-T), 86 patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndromes, and six patients with secondary AML after previous chemotherapy. Median age was 58 years (range: 18-76 years). Forty-nine patients (45%) achieved a complete remission (CR) after two induction cycles with idarubicin, ara-C, and etoposide, 52% of them aged </=60 years and 35% aged >60 years (p=0.06). After two consolidation courses, patients were randomized to four cycles of either high- or low-dose IL-2. Patients aged up to 55 years with an HLA-identical sibling donor were eligible for allogeneic bone marrow transplantation. The median relapse-free survival was 12.5 months, with a probability of ongoing CR at 6.5 years of 19%. Overall survival of all patients was 8 months, and 21 months for the CR patients. Median survival was significantly longer among patients aged </=60 years than among the older patients (16 vs 6 months, p<0.001). Median duration of survival and relapse-free survival were not statistically different in the two IL-2 treatment arms.

Acute Disease↗

PubMed1999

Association between structural and numerical chromosomal aberrations in acute myeloblastic leukemia: a study by RT-PCR and FISH in 447 patients with de-novo AML.

We analyzed 447 patients with de novo AML using alpha-satellite probes for the chromosomes 7, 8, X, and Y and RT-PCR for t(8;21), t(15;17) and inv(16). In 130/447 patients (29%) chromosomal aberrations were found. Thirty-three patients (7%) had a t(8;21); 11 of these had the additional loss of a sex chromosome (p<0.001) and two a trisomy 8. Twenty-nine patients (6%) had a t(15;17); four of these had a trisomy 8. Sixteen patients (4%) displayed an inv(16); four of these had a trisomy 8. Twenty-two patients (5%) had a sole trisomy 8 and one patient the combination of trisomy 8 and trisomy X. Five patients (1%) displayed the loss of a Y-chromosome as the sole abnormality and two patients had a sole trisomy X. In 22 patients (5%) a monosomy 7 was found, and in none of these patients were additional chromosomal aberrations detected by RT-PCR (p < 0.05). In conclusion, trisomy 8 and the loss of a gonosome are frequently associated with structural chromosomal aberrations with a significant association of -X/Y and t(8;21). The absence of these genomic lesions in AMLs with monosomy 7 suggests that the monosomy 7 has a specific role in the development of these leukemias and their clinical course.

Adolescent↗

PubMed1988

Induction of proliferation of acute myeloblastic leukemia (AML) cells with hemopoietic growth factors.

Like their normal counterparts, leukemic blasts have recently been shown to respond to hemopoietic growth factors in both suspension culture and in semisolid media. In the present study, we have evaluated the proliferative response of 35 AML cases to colony-stimulating factors (CSFs) containing conditioned media derived from the human cell lines GCT, 5637, MO and MG U87, and to human recombinant IL-1 (rh-IL1), IL-3 (rhIL-3), GM-CSF (rhGM-CSF) and G-CSF (rhG-CSF). In the great majority of cases, an increase of 3H-thymidine (3H-TdR) uptake was obtained in response to at least one conditioned medium. The labeling index (LI) and the growth fraction (GF), evaluated in a restricted group of cases, were also increased by the growth factors, suggesting that they act by recruiting leukemic cells in cycle from the resting compartment. The ability of blast populations to form colonies was also studied. Conditioned media were found to induce or significantly increase the clonogenic capacity in 20 cases out of 22. The response of leukemic cells to human recombinant CSFs and rhIL-1, used alone or in combination, was also assayed. The results, in agreement with those obtained with conditioned media, show that each leukemic case displays a different pattern of response to CSFs, and that optimal growth conditions must be individually assessed. The possibility of increasing the fraction of cycling cells in AML populations may represent a way to render them more sensitive to cytostatic agents, with a view to new therapeutic strategies.

Adolescent↗

PubMed1992

Myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) with myelofibrosis.

Acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) enter rarely in the differential diagnosis of myelofibrosis (MF). MF of marked intensity, resulting in either "dry taps" or non-representative smears, is encountered in approximately 10% of cases. MF may be observed in any type of AML, most frequently in acute megakaryoblastic leukemia (M7). Apart from some typical cases of MDS, MF is associated with cases of acute myelodysplasia with myelofibrosis (and a major megakaryocytic component). This syndrome has been described under various headings: acute or malignant myelosclerosis, and acute MF. It should be distinguished from M7 and from myeloproliferative syndromes.

Acute Disease↗

PubMed1993

Identification of masked and variant Ph (complex type) translocations in CML and classic Ph in AML and ALL by fluorescence in situ hybridization with the use of bcr/abl cosmid probes.

In the present study, three chronic myelogenous leukemia (CML) patients with variant Philadelphia (Ph) chromosomes (complex types), two CML patients with a masked Ph, one case with Ph positive acute lymphocytic leukemia (ALL), and one with Ph positive acute myelocytic leukemia (AML) were analyzed by standard cytogenetic techniques (G-banding), Southern blot studies, and fluorescence in situ hybridization (FISH) procedures using probes from portions of the bcr and abl genes. It has been previously shown that this FISH approach could detect the bcr/abl fusion event in CML patients with classic or variant (simple type) Ph. Our results demonstrate that this FISH assay can also detect the bcr/abl fusion status in CML patients with masked or variant (complex type) Ph chromosomes and in some patients with Ph positive ALL or AML.

Adult↗

PubMed1994

Acute myeloid leukemia (AML-M1) with multiple trisomies and t(8;21)(q22;q22).

Cytogenetic analysis of an acute myeloid leukemia (AML-M1) showed the karyotype 53,XY, +6, +8,t(8;21)(q22;q22), +9, +10, +13, +19, +21. Only one AML with a massively hyperdiploid karyotype (> 50 chromosomes) and t(8;21) has been published before. A comparison of the two cases reveals similarities both with regard to the morphologic subtype (M1) and to which chromosomes were trisomic (+6, +8, +13, +19, and +21 were found in both cases). We surmise that the t(8;21) was the primary chromosomal abnormality and that the set of multiple trisomies occurred secondarily; this pattern of clonal evolution may have favored a more immature leukemic phenotype in these two cases than is regularly seen in t(8;21)-associated leukemias.

Child↗

PubMed1989

Auer rods and myeloperoxidase: an approach for investigating changes at the molecular level in acute myeloid leukaemia (AML).

Auer rods are cytoplasmic inclusions found only in the leukaemic cells of some cases of acute myeloid leukaemia (AML). The ultrastructure of Auer rods is different in different sub-types of the disease and it is suggested here that this may be a consequence of the Auer rods consisting of different crystalline forms of the enzyme myeloperoxidase. There is statistical evidence to indicate that patients with Auer rods have a more favourable prognosis than those without. It is proposed that an investigation of the factors that determine the form, if any, of the crystallisation of myeloperoxidase will lead to a better understanding of the molecular events underlying the different types of AML. In the long term this may in turn lead to a therapeutic advance.

Humans↗

PubMed1992

Radiation and heat sensitivity of human T-lineage acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) clones displaying multiple drug resistance (MDR).

The hyperthermia as well as radiation responses of multidrug resistant (CEM/VLB100 with classical MDR and CEM/VM-1 with atypical MDR), methotrexate resistant (CEM/MTX) subclones of CCRF-CEM T-lineage ALL cell line were compared with those of a drug sensitive (CEM-1-3) subclone from the same parent cell line. Also analyzed were the hyperthermia as well as radiation responses of multidrug resistant (HL60/AR) and drug sensitive subclones of the HL60 AML cell line. Notably, the drug resistant subclones of CEM and HL60 were as sensitive to hyperthermia as were the drug sensitive subclones. Importantly, no thermotolerant plateau was observed in the hyperthermia survival curves of the drug resistant subclones, indicating that drug/multidrug resistance is not associated with a greater likelihood of thermal tolerance development during hyperthermia. Similarly, the drug resistant CEM and HL60 subclones were not more radiation resistant than the drug sensitive subclones. Thus, the classical or atypical forms of multidrug resistance or methotrexate resistance of the analyzed leukemic cell lines were not associated with radiation resistance. Furthermore, the radiation survival curves of the drug resistant subclones lacked a distinct initial shoulder and their n values were not greater than those of the drug sensitive subclones, suggesting that multidrug resistance is not associated with an increased ability to repair or accumulate sublethal radiation damage. Our findings provide evidence that there is no apparent association between drug/multidrug resistance and heat or radiation sensitivity of CEM T-lineage ALL or HL60 AML leukemia cells. The results of this study indicate that acquired resistance to methotrexate, vinblastine, vincristine, etoposide, actinomycin-D, adriamycin, or daunomycin, or pleiotropic multidrug resistance do not necessarily confer radiation resistance for human leukemic cells.

Adaptation, Physiological↗