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PubMed1993

Influence of schedule on regulated sensitivity of AML blasts to cytosine arabinoside.

Regulatory molecules that affect the growth culture of blast cells from acute myeloblastic leukemia (AML) may also alter drug sensitivity, a phenomenon that may be called regulated drug sensitivity. Previous studies have shown: (i) blast cells exposed to retinoic acid before cytosine arabinoside (Ara-C) usually show increased sensitivity, but after some retinoic acid exposure times, sensitivity may be decreased; (ii) factor-sensitive or responsive blasts cultured with granulocyte colony-stimulating factor (G-CSF) are regularly more Ara-C-sensitive than when cultured with granulocyte-macrophage CSF (GM-CSF). This paper is concerned with the effects of schedule on drug sensitivity as regulated by either retinoic acid or the myelopoietic growth factors, G-CSF and GM-CSF. We measured the effects of retinoic acid on the sensitivity of blasts cells from the two continuous AML lines to Ara-C or arabinofuranosyl 5-azacytosine (Ara-AC). Cells from seven patients with AML were tested for Ara-C sensitivity in conjunction with retinoic acid. The cells were treated with retinoic acid before or after administration of the drug. Both increases and decreases in Ara-C sensitivity were seen for both schedules. Consistent increases in Ara-C sensitivity were obtained when retinoic acid was included in the methylcellulose cultures used to determine clonogenic cell recovery at each drug dose. In studies of growth factors, a single factor-dependent cell line (OCI/AML-5) was used to compare the effects of G-CSF and GM-CSF on Ara-C sensitivity. An experimental design was used that permitted factors to present in culture for 24 h before Ara-C, during the next 24 h period with the drug, for a subsequent day in suspension without drug, and during the 5-7 days required for colony formation in methylcellulose cultures. G-CSF and GM-CSF were most effective in increasing or decreasing Ara-C, respectively, when the factor under test was included in the methylcellulose cultures. Thus, like retinoic acid, growth factors influenced drug sensitivity when they were present after the drug had been removed. These data, therefore, are compatible with the hypothesis that repair mechanism may contribute to regulated drug sensitivity.

Acute Disease↗

PubMed1995

[Clinical characteristics and poor outcomes in patients with de novo AML with trilineage myelodysplasia].

De novo AML with trilineage myelodysplasia (AML/TMDS) is reported to account for 10-15% of de novo AML and respond poorly to conventional intensive chemotherapy, In our series, 12 (25%) of 48 patients with de novo AML were diagnosed as AML/TMDS. We found that the platelet count was significantly higher (p < 0.05), and the blast percentage of the bone marrow was significantly lower (p < 0.05) in the AML/TMDS group than in the AML/non-TMDS group. Sex ratio, age, WBC and RBC count did not significantly differ between the two groups. The immunological markers and the myeloperoxidase positivity of the blasts of AML/TMDS varied widely. The CR rate was 66.7% in the AML/TMDS group and 83.3% in the AML/non-TMDS group. Dysplastic changes were still detected in the bone marrow smears in 7 of 8 AML/TMDS cases who achieved complete remission. The AML/TMDS group showed significantly shorter CR duration (median; 169 days) and survival (median; 511 days, p < 0.05). However, in two cases which underwent allogeneic bone marrow transplantation (allo-BMT) during early relapse phase the disease-free survival has extended over 4 years and 2 years 8 months, respectively. Thus, we would like to propose that allo-BMT should be performed as early as possible to overcome poor outcome of AML/TMDS.

Adolescent↗

PubMed1995

Inhibition of bcl-2 with antisense oligonucleotides induces apoptosis and increases the sensitivity of AML blasts to Ara-C.

We have previously shown that blasts from acute myeloid leukaemia (AML) patients which grow autonomously in culture have high bcl-2 expression which in turn has been linked to a poor clinical response to chemotherapy. The bcl-2 protein promotes cell survival by preventing the onset of apoptosis or programmed cell death following growth-factor deprivation. Bcl-2 has also been shown to be responsible for chemo-resistance in human leukaemic cell lines. Here we have investigated the role of bcl-2 expression in mediating resistance to apoptosis induced by cytosine arabinoside in vitro. The blasts from 17 AML patients exhibiting autonomous growth in a blast cell colony assay and expressing high levels of bcl-2 protein were studied. Incubation of the blasts with antisense oligonucleotides directed against bcl-2 mRNA resulted in a significant decrease in expression of the bcl-2 protein in seven of the 17 samples. In these seven cases the decreased expression of bcl-2 was accompanied by increased apoptosis and the susceptibility of the blasts to apoptosis induced by Ara-C was increased in the presence of bcl-2 antisense. As a high level of bcl-2 defines a group of AML patients who exhibit a poor response to chemotherapy, the demonstration that chemosensitivity of a significant proportion of these patients can be increased by bcl-2 antisense suggests this approach may have clinical potential.

Apoptosis↗

PubMed1995

Absence of point mutations in the extracellular domain of the alpha subunit of the GM-CSF receptor in a series of patients with acute myeloid leukemia (AML).

The GM-CSF receptor belongs to the cytokine receptor superfamily. The high-affinity receptors of this class are lacking intrinsic tyrosine kinase domains. The GM-CSF receptor consists of alpha and beta subunits. The beta subunit is shared with the receptors of IL-3 and IL-5. In addition to the membrane bound forms the receptors have been found to possess soluble isoforms. Since retroviral infection of the human GM-CSF dependent cell line, TF-1, leads to factor independent growth by increased expression of the GM-CSF receptor alpha chain in a subgroup of infected clones, we were interested in studying the role of this chain in human AML. Further considering that a point mutation in the extracellular domain of the erythropoietin receptor, also a member of the cytokine receptor superfamily, resulted in constitutive activation of a murine cell line, we investigated the possibility that a point mutation of the GM-CSF receptor was responsible for autonomous growth of AML cells. We sequenced a segment of the receptor coding for the extracellular domain of the alpha subunit. cDNA was prepared from peripheral blood or bone marrow cells from 24 patients with AML, from four patients with MDS and from three human myeloid cell lines. The region of interest was amplified with two rounds of PCR reactions with nested primers, covering five overlapping fragments, and directly sequenced using a non-radioactive technique. No point mutations were found in the investigated samples. Thus, point mutations in this segment of the GM-CSF receptor gene do not seem to play an important role in the transformation process of human acute leukemia.

Base Sequence↗

PubMed1994

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↗

PubMed1994

[Diagnosis and treatment of acute undifferentiated leukemia and AML-MO].

To characterize AML-MO (MO) and acute undifferentiated leukemia (AUL) clinically, questionnaires were sent to nationwide hematology departments in May and August 1993. From 65 institutions, 71 MO cases (2.2% of acute leukemias, 3% of AML) and 19 AUL cases (0.4% of acute leukemias) were registered. Median age was 55 (15-81) years for MO and 38.5 (15-71) years for AUL, and the M/F sex ratio was 44:27 for MO and 19:2 for AUL. Of 48 cases examined for chromosome analysis, 24 (50%) were abnormal karyotypes. Of 15 cases examined for electron microscopic myeloperoxidase (MPO), 10 (67%) were positive, and of 9 cases examined for cytoplasmic antigen by anti-MPO antibody, 7 (78%), were positive. Examination of TdT, surface antigen of CD7 and CD34 were performed in 22, 61 and 43 cases and each positivity was 59, 51 and 86%, respectively. 3 of 18 cases showed rearrangement of immunoglobulin heavy chain gene and 2 of 13 cases showed rearrangement of T cell receptor beta gene. With the first-line induction chemotherapy, complete remission (CR) was obtained in 34 of 67 MO cases and in 7 of 18 AUL cases. Median CR duration and median survival for MO cases were 361 and 387 days and those for AUL were 541 and 578 days, respectively. The remission rates were 61% for 54 cases treated with AML chemotherapy regimens and 38% for 13 cases treated with ALL chemotherapy regimens. 9 cases of MO and AUL who received bone marrow transplantation (BMT) had excellently good prognosis compared with non-BMT group.

Adolescent↗

PubMed1993

Acute myeloid leukemia (AML) can be oligoclonal.

Acute myeloid leukemia (AML) is usually thought to represent a monoclonal disease. Among 45 cases of newly diagnosed AML we found rearranged bands in 14 cases using the Southern blot methodology and immunoglobulin (Ig) joining region (JH) or T-cell receptor (TCR beta) probes. In three patients, the findings indicated an oligoclonal disease. One case was characterized by several bands in the JH blot, some of which reappeared at different time points during remission. A second case had monoclonally rearranged Ig-JH sequences in the bone marrow but exclusively germline configuration in DNA from peripheral blood cells despite the presence of 84% blasts. A third case was characterized by two different, Ig-JH and c mu gene rearranged cell populations at diagnosis but relapsed with a germline pattern without reappearance of the previous clones. These data indicate that AML may differentiate along different lineages with predominant appearance of one or the other subclone in the course of the disease.

Blotting, Southern↗

PubMed1993

The mitogenic response of AML blasts to tumor necrosis factor-alpha requires functional c-jun/AP-1.

The c-jun proto-oncogene belongs to the family of immediate early response genes and is inducible by serum growth factors and Tumor Necrosis Factor (TNF). In the present study we have addressed the role of c-jun for the mitogenic response of primary acute myelogenous leukemia (AML) blasts to TNF-alpha. Our data indicate that TNF-alpha treatment of these cells is associated with transcriptional activation of c-jun and accumulation of c-jun mRNA. In order to elucidate the role of c-jun for TNF-mediated growth stimulation, an antisense (AS) oligomer directed towards the translation initiation site of c-jun was instrumental. Uptake studies of oligonucleotides showed that incorporation of oligomers was maximal at 4 hours. Oligodeoxynucleotides remained stable in these cells for up to 24 hours. Treatment of AML blasts with the AS oligonucleotide resulted in intracellular duplex formation followed by efficient translation blockade of c-jun/AP-1. In contrast, sense (S) and none-sense (NS) oligodeoxynucleotides failed to form intracellular duplexes and also did not interfere with translation of c-jun/AP-1, suggesting specific elimination of c-jun/AP-1 by the AS oligomer. AML blasts cultured in the presence of AS to c-jun, but not of S or NS, failed to proliferatively respond to TNF-alpha stimulation. Taken together, our results indicate that activation of c-jun/AP-1 plays a pivotal role in the signaling cascade initiated by TNF which leads to a proliferative response of its target cells.

Base Sequence↗

PubMed1993

Inhibitory effect of interleukin-4 on the proliferation of acute myeloid leukemia cells with myelo-monocytic differentiation (AML-M4/M5); the role of interleukin-6.

Since interleukin-4 (IL-4) specifically inhibits monocytic colony formation in human bone marrow cultures, we investigated whether a similar inhibition could be observed in cultures of optimally stimulated acute myeloid leukemia cells with myelomonocytic differentiation (AML-M4/M5). Sensitivity to IL-4 was tested in 19 cases of AML-M4/M5, using both a 3H-thymidine incorporation assay and a clonogenic assay. Proliferation was stimulated with a combination of IL-3, granulocyte-monocyte colony-stimulating factor (GM-CSF), and conditioned medium from phytohemagglutinin-stimulated leukocytes (PHA-CM). In 13 out of 14 evaluable cases, IL-4 inhibited 3H-thymidine incorporation; stimulation was seen in one case. Using a clonogenic assay, IL-4 inhibited colony formation in all evaluable cases (n = 7). Addition of IL-6 did not alter the observed inhibition by IL-4 in 9 out of 10 cases tested. We conclude that IL-4 inhibits the proliferation of optimally stimulated AML-M4/M5 cells in most cases tested, and that this effect is not generally caused by inhibition of autocrine IL-6 production.

Cell Division↗

PubMed1996

Expression of PKC isozyme and MDR-associated genes in primary and relapsed state AML.

For investigation of relative differences in mRNA expression levels and of correlations in the expression of genes possibly involved in multidrug resistance (MDR) of acute myelogenous leukemias (AML), a complementary DNA polymerase chain reaction (cDNA-PCR) analysis was established for the genes encoding MDR1/P-glycoprotein, the multidrug resistance-associated protein (MRP), topoisomerase II alpha, topoisomerase II beta, topoisomerase I, glutathione S-transferase pi, protein kinase C (PKC) isozymes alpha, beta 1, beta 2, epsilon, eta, theta and cyclin A. In a first descriptive study comprising samples of childhood or adult AML we calculated the mean values from primary (n=14) or relapsed (n=23) states of the diseases, respectively. We found in the latter significant increases of MDR1, MRP, gst pi, and PKC theta gene expression. MDR1 and MRP gene expression levels were generally correlated (rs= +0.4128, P<0.02, n=37), as well as topoisomerase II alpha and cyclin A gene expression levels (rs= +0.8727, P<0.0001, n=35). Within the group of relapsed state AML a significant negative correlation between the gene expression levels of MDR1 and topoisomerase II alpha (rs= -0.5500, P<0.01, n=22) was observed. Remarkably, highly significant positive correlations were found for MDR1/PKC eta (rs= +0.5560, P<0.001, n=32), MRP/PKC theta (rs= +0.6573, P<0.0001, n=34) and MRP/PKC eta (rs= +0.5241, P<0.005, n=32).

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Treatment of refractory AML.

Refractory AML is variously defined. MD Anderson data indicate that patients with AML that stayed in first remission for less than 2 years are incurable with standard chemotherapy regimens, hence meriting a definition of refractory; the prognosis of patients whose first remissions are longer is on average similar to that of untreated patients. Within the refractory group, Hiddeman et al' s definition (Leukemia 1990; 4: 184-188) is elaborated to account for the number of courses of initial therapy and for response to prior salvage regimens. If patients with refractory AML cannot receive an allogeneic transplant, the standard of therapy should be investigational chemotherapy regimens. A new Bayesian pre-phase II designed is described for use in testing such regimens.

Adolescent↗

PubMed1996

De novo AML with dysplastic hematopoiesis: cytogenetic and prognostic significance.

Dysplastic hematopoiesis is the morphological hallmark of myelodysplastic syndromes. Dysplastic features in one or more lineages are also found frequently in bone marrow aspirates from patients with de novo AML and have been associated with an unfavorable prognosis. We asked whether dyshematopoiesis is an independent prognostic factor or an indicator of unrecognized secondary leukemia, identified by characteristic chromosomal abnormalities. Bone marrow aspirates from 102 patients with newly diagnosed AML were analyzed. Morphological analysis was obtained in all patients, flow cytometric analysis in 96 and successful cytogenetic analysis in 65 bone marrow aspirates. Dysgranulopoiesis (DysG) was found in 55, dysmegakaryopoiesis (DysM) in 32 and dyserythropoiesis (DysE) in 23 patients. Decreased side scatter signals of neutrophils in the flow cytometric analysis (DysS) were detected in 32 patients. DysG and DysS showed a highly significant correlation (P = 0.0005). DysG was an adverse negative prognostic factor for remission rate and event-free survival (P = 0.04, P = 0.02). An unfavorable karyotype was associated with a significantly lower chance for event-free survival (P = 0.002). The incidence of an unfavorable karyotype was significantly higher in patients with DysG (P = 0.01), DysM (P = 0.02) and DysS (P = 0.01). In patients with an unfavorable karyotype, dysplasia had no additional prognostic influence, however, in patients with a normal, favorable or prognostically uncertain karyotype DysG remained a predictor of lower remission rate (P = 0.03). We conclude that dysgranulopoiesis, dysmegakaryopoiesis and decreased side scatter signals of neutrophils are indicators of secondary leukemias in bone marrow aspirates from patients with de novo AML.

Bone Marrow↗

PubMed1996

Expression pattern of WT1 and GATA-1 in AML with chromosome 16q22 abnormalities.

WT1 is a tumor suppressor gene that can repress transcription of many growth-factor and growth-factor receptor genes. We quantitated WT1 expression levels in 62 acute myelogenous leukemia (AML) samples and found that 82% strongly expressed WT1. WT1 expression levels are highest in the undifferentiated and granulocytic French-American-British (FAB) subclasses and lower in the monocytic subclasses. WT1 was strongly expressed in normal CD34+ bone marrow (BM) stem cells but only weakly or not expressed in normal mature blood cells. This suggests that WT1 gene expression is associated with immature cells, which have high proliferative capacities. Previous studies of WT1 gene regulation showed that GATA-1 may regulate WT1 expression. To understand the relationship between WT1 and GATA-1 expression in leukemia, we examined the expression pattern of GATA-1 in the cells described above. Overall, AML samples expressed significant amounts of both WT1 and GATA-1. However, AML samples with 16q22 abnormalities, presumably interrupting the core binding factor (CBF) beta gene expressed lower than normal levels of GATA-1 but high levels of WT1. Our data suggest that the transcription factor CBF beta may be important for GATA-1 gene regulation. Thus, WT1 expression varied in different FAB subclasses, and GATA-1 expression was strongly affected by the presence of chromosome 16q22 abnormalities.

Chromosome Aberrations↗

PubMed1996

Autologous versus allogeneic BMT in AML: the European experience. Report of the EBMT--Pediatric Diseases Working Party.

The Austrian-German-Italian (AGI) Pediatric Bone Marrow Transplantation Registry includes now data of 520 patients grafted for acute myeloid leukemia (AML) by autologous and allogeneic stem cells. In first complete remission (CR1) 145 patients with allografts had a possibility of event free survival (pEFS) of 0.57 and 140 patients with autografts a pEFS of 0.46. In second complete remission (CR2) autografted patients (n = 70) had a pEFS of 0.36 and allogeneic patients (n = 41) of 0.34. Patients with no CR went worse (allogeneic pEFS 0.15 n = 37; autologous pEFS 0.17 n = 6). Therefore, from the European data the following conclusions can be drawn: neither in CR1 nor in CR2 any statistical advantage for a particular transplantation type can be found. To assess the value of transplantation with family mismatch donors or matched unrelated donors (MUD) basing on these data pool is not possible. The following decisions should be reached: 1) BMT for AML with mismatched or unrelated donors should be done only within cooperative European trials. 2) Generally accepted definitions of indications for BMT in AML are needed. 3) Study protocols concerning conditioning are necessary.

Bone Marrow Transplantation↗

PubMed1997

Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council.

The relative efficacy and toxicity of the chemotherapeutic agents thioguanine (6TG) and etoposide (VP16) were assessed by a randomized comparison of the DAT (daunorubicin, cytarabine, thioguanine) versus ADE (daunorubicin, cytarabine, etoposide) regimens in the Medical Research Council's 10th acute myeloid leukaemia trial (MRC AML 10), which was open to patient entry from May 1988 to April 1995. In this, the largest reported trial of AML therapy to date, 1,857 eligible patients, mostly less than 56 years old, were randomized: 929 (including 143 children under 15 years old) were allocated to DAT and 928 (143 children) to ADE. The two groups were well matched for presentation features. The complete remission (CR) rate was 81% with DAT and 83% with ADE (P = .3). The percentages of remitters achieving remission after 1, 2, or more than 2 courses were 70%, 22%, and 8% for DAT and 74%, 21%, and 5% for ADE. The percentages failing to achieve a CR due to resistant disease were 11% with DAT versus 9% with ADE (P = .07). There was a slightly higher death rate in CR during consolidation chemotherapy with ADE (9%) than with DAT (6%) (P = .06). Patients receiving DAT took slightly but significantly longer to recover from neutropenia and thrombocytopenia but the median number of days in hospital were similar in each group. ADE patients experienced slightly more severe nonhematologic toxicity. There was also no significant difference between the groups in the longer-term measures of efficacy: disease-free survival at 6 years from CR was 42% (+/-4) for DAT and 43% (+/-4) for ADE (P = .8); relapse rate at 6 years was 50% (+/-4) for DAT and 49% (+/-5) for ADE (P = .6); survival at 6 years was 40% (+/-4) for both DAT and ADE (P = .9). Subgroup analysis failed to show any benefit for etoposide in patients with monocytic or myelomonocytic disease, or in any other diagnostic subgroup. In conclusion, DAT and ADE both achieve high remission rates and good long-term survival, and are equally effective chemotherapy regimens for the treatment of AML patients aged up to 55 years.

Acute Disease↗

PubMed1997

Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group.

We conducted a prospective randomized multicenter clinical trial comparing the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjunct to intensive chemotherapy in patients of 61 years and older with untreated newly diagnosed acute myeloid leukemia (AML). Patients were randomized to either receive daunomycin-cytosine arabinoside with GM-CSF or daunomycin-cytosine arabinoside (control arm). Based on the rationale that GM-CSF might sensitize the leukemic cells to the cytotoxicity of chemotherapy as well as enhance white blood cell regeneration, GM-CSF was given during chemotherapy as well as after chemotherapy. Patients were treated with one, and in case of a partial response, with two remission induction cycles. When a complete remission was attained they received one additional cycle of consolidation therapy. Of 318 evaluable patients with a median age of 68 years, 157 were randomized to receive GM-CSF and 161 were assigned to control therapy. The effect of GM-CSF on treatment was evaluated according to intention-to-treat. Complete remission was achieved in 56% of the patients in the GM-CSF group and 55% of the control patients (P = .98). Recovery of neutrophils was significantly faster in GM-CSF-treated patients. The median time of recovery of neutrophils towards 0.5 x 10(9)/L was 23 days in the GM-CSF group versus 25 days in the control group (P = .0002) with the percentages of patients who recovered being 81% and 71%, respectively. With a median follow-up of 36 months, the probabilities of survival at 2 years after randomization were estimated at 22% for individuals assigned to the GM-CSF treatment as well as for control patients (P = .55). Disease-free survival at 2 years compared 15% and 19% for the two treatment groups (P = .69). The number of nights spent in the hospital, number of transfusions, and frequencies and types of hemorrhages and infections did not differ either. The cytogenetic results at diagnosis of this study in elderly AML shows that there is a relatively high numerical representation of patients with abnormal cytogenetics (55% of documented cases), who showed significantly inferior response rates and survival duration. We conclude that, except for a faster neutrophil recovery, GM-CSF during and after induction chemotherapy does not improve the clinical outcome of elderly patients with AML.

Acute Disease↗

PubMed1995

High remission rate, short remission duration in patients with refractory anemia with excess blasts (RAEB) in transformation (RAEB-t) given acute myelogenous leukemia (AML)-type chemotherapy in combination with granulocyte-CSF (G-CSF).

A study was made to determine CR rate, response duration and survival in patients with RAEB or RAEB-t given AML-type chemotherapy, in particular the newer agents idarubicin and fludarabine. Eighty-five adults (58 RAEB-t, 27 RAEB) received either IA (idarubicin 12 mg/m2 daily on days 1-3, ara-C 1.5 g/m2 daily on days 1-4 CI), FA (fludarabine 30 mg/m2 daily on days 1-5, ara-C 2 g/m2 daily on days 1-5) or FLAG (FA + G-CSF 400 micrograms/m2 daily from day-1 until CR). IA was given exclusively to patients with better prognosis (as assessed by pretreatment karyotype), while FA and FLAG were given first to patients with worse and then to those with better prognosis. In remission, patients received lower doses of the same regimens for 6-12 months. The 85 patients comprise the largest reported series of RAEB or RAEB-t patients given AML-type chemotherapy. Their median age was 61 years, 33% had chromosome 5 or 7 abnormalities (-5/-7), and 55% were treated in laminar air flow rooms. The CR rate was 66%. While rates were highest in younger patients with a normal karyotype, CR rates in excess of 50% were also obtained in patients over age 60 (27/47; 57%) and in patients with -5/-7 (17/29; 59%). In 11 of the 14 cytogenetically abnormal patients in whom cytogenetic analysis was repeated at the time of CR, only normal metaphases were found. In the remaining 3 the number of abnormal metaphases was substantially reduced. However, the probability of continued CR was low (e.g. 452 +/- 0.08 at 12 months), and the only patients alive in CR beyond two years were patients under age 60 without -5/-7 and with RAEB-t. Survival probability was 0.35 +/- 0.05 at one year. Eight of 56 patients died in CR. While current AML-type chemotherapy can produce higher CR rates than is perhaps usually appreciated, in some patients with RAEB or RAEB-t (e.g. older patients with -5/-7) the brevity of the remissions and the risk entailed suggest that new post-remission therapies are needed to make this approach generally worthwhile.

Adult↗

PubMed1996

Quantitative measurements of the efficacy of new anti-cancer agents on fresh human AML cells by using multivariate flow analysis.

The testing of new human leukemia-specific drugs for activity against primary acute myeloid leukemia (AML) blasts is severely limited by the low and variable clonogenic potential of primary human leukemias in culture. To circumvent this problem, we have modified a previously described flow cytometric approach to permit the simultaneous determination of live/dead cells, and the quantitation of the surviving cell fraction as a ratio of viable cells in treatment and control groups. The method utilizes the combination of calceinAM as a probe for intracellular esterase activity (green fluorescence,) which has the advantage over carboxyFDA of pH insensitivity and superior signal-to-noise ratio, and propidium iodide (red fluorescence) as an indicator of plasma membrane integrity. Suspension cultures of AML blood and marrow samples from patients were treated with known active agents as well as several new agents arising from a clonogenic disk assay screen. Quantitative dose-response values obtained from surviving cell fractions assayed by flow cytometry at 24 h following drug exposure demonstrated the utility of this assay for quantitating drug-induced cytotoxic effects on primary human AML cells in short-term culture.

Animals↗