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PubMed2003

Analysis of t(9;11) chromosomal breakpoint sequences in childhood acute leukemia: almost identical MLL breakpoints in therapy-related AML after treatment without etoposides.

The translocation t(9;11)(p22;q23) is a recurring chromosomal abnormality in acute myeloid leukemia (AML) fusing two genes designated as MLL and AF9. Within MLL, almost all rearrangements cluster in an 8.3-kb restricted region and fuse 5' portions of MLL to a variety of heterologous genes in various 11q23 translocations. AF9 is one of the most common fusion partners of MLL. It spans more than 100 kb, and two breakpoint cluster regions (BCRs) have been identified in a telomeric region of intron 4 (BCR1) and within introns 7 and 8 (BCR2). We investigated 11 children's bone marrow or peripheral blood samples (3 AML, 5 t-AML, 2 ALL, 1 ALL relapse) and two cell lines (THP-1 and Mono-Mac-6) with cytogenetically diagnosed translocations t(9;11). By use of an optimized multiplex nested long-range PCR assay, a breakpoint-spanning DNA fragment from each sample was amplified and directly sequenced. In four patients and two cell lines, the AF9 breakpoints were located within BCR1 and in two patients within BCR2, respectively. However, in five patients the AF9 breakpoints were found outside the previously described BCRs within the centromeric region of intron 4 and even within intron 3 in one case. All five patients with a secondary AML, who had not received etoposides during treatment of the primary malignant disease, revealed almost identical MLL breakpoints very close to a breakage hot spot inducible by topoisomerase II inhibitors or apoptotic triggers in vitro. Sequence patterns around the breakpoints indicated involvement of a "damage-repair mechanism" in the development of t(9;11) similar to t(4;11) in infants' acute leukemia.

Acute Disease↗

PubMed2002

Identification of cytogenetic subclasses and recurring chromosomal aberrations in AML and MDS with complex karyotypes using M-FISH.

Complex chromosomal aberrations (CCAs) can be detected in a substantial proportion of AML and MDS patients, de novo as well as secondary or therapy-related, and are associated with an adverse prognosis. Comprehensive analysis of the chromosomal rearrangements in these complex karyotypes has been hampered by the limitations of conventional cytogenetics. As a result, our knowledge concerning the cytogenetics of these malignancies is sparse. Here we describe a multiplex-FISH (M-FISH) study of CCAs in 36 patients with AML and MDS. M-FISH generated a genome-wide analysis of chromosomal aberrations in CCAs, establishing several cytogenetic subgroups. -5/5q- was demonstrated in the majority of patients (86%). Other rearrangements (present with or without -5/5q-) included: deletion of 7q (47%), 3q rearrangements (19%), and MLL copy gain or amplification (17%). These genetic subgroups seem to display biological heterogeneity: MLL copy gain or amplification in association with 5q- was detected only in AML patients and was significantly associated with extremely short survival (median overall survival: 30 days, P = 0.0102). A partially cryptic t(4;5)(q31;q31), a balanced t(1;8)(p31;q22), and an unbalanced der(7)t(7;14)(q21;q13) were detected as possible new recurrent rearrangements in association with CCAs. Novel reciprocal translocations included t(5;11)(q33;p15)del(5)(q13q31) and t(3;6)(q26;q25). We conclude that AML and MDS with CCAs can be subdivided into molecular cytogenetic subclasses, which could reflect different clinical behavior and prognosis, and that three recurrent chromosomal aberrations are associated with karyotype complexity.

Acute Disease↗

PubMedDate not supplied

Triple combination of retinoic acid + low concentration of cytosine arabinoside + hexamethylene bisacetamide induces differentiation of human AML blasts in primary culture.

Differentiation induction therapy provides an alternative therapeutic approach for patients with acute myeloid leukemia (AML) who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy. The effect of a triple combination of retinoic acid (RA) + low concentration of cytosine arabinoside (Ara-C) + hexamethylene bisacetamide (HMBA) on differentiation of blasts from 24 AML patients was studied. Non-adherent mononuclear cells were seeded at a concentration of 5 x 10(5) cells per ml in 24-well tissue culture plates containing RPMI 1640 culture medium with 20 per cent fetal calf serum and 10 per cent 5637-conditioned medium and incubated with 10(-6) M retinoic acid, 10(-6) M cytosine arabinoside and/or 2 mM hexamethylene bisacetamide for six days at 37 degrees C in a humidified incubator under 5 per cent CO2. Morphological, cytochemical and functional differentiation into mature cells were induced in blasts from 22 out of the 24 AML patients following exposure to the triple combination of 10(-6) M RA + 10(-6)M Ara-C + 2 mM HMBA in primary culture. These effective results justify a clinical trial of such triple combination for AML patients who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy.

Acetamides↗

PubMed1991

Growth regulation of the AML-193 leukemic cell line: evidence for autocrine production of granulocyte-macrophage colony-stimulating factor (GM-CSF), and inhibition of GM-CSF-dependent cell proliferation by interleukin-1 (IL-1) and tumor necrosis factor (TNF alpha).

The human leukemic cell line AML-193 was tested for its proliferative response to endogenously produced autocrine factors and to a variety of cytokines and colony-stimulating factors. Cells grown in the absence of GM-CSF incorporated tritiated thymidine, and this was partially reversed by adding neutralizing anti-GM-CSF antibodies to the culture medium, suggesting that it was due, at least in part, to autocrine GM-CSF production. This was confirmed by immunopurification of a GM-CSF-like activity from cell supernatant of AML-193 cells grown in serum free medium in the absence of exogenous GM-CSF. When AML-193 cells were cultured with GM-CSF in combination with other cytokines, Interleukin-1 alpha and beta (IL-1 alpha and beta), Interleukin-3 (IL-3), Interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF) and tumor necrosis factor alpha (TNF alpha), none of them affected the concentration of GM-CSF required to induce 50% of maximum proliferation (D50). However, the maximum proliferation induced by GM-CSF alone was drastically decreased by IL-1 alpha, IL-1 beta and TNF alpha. Inhibition caused by exposure of the AML-193 to IL-1 for up to 24 hr was reversible, ruling out a direct cytotoxic effect.

Cell Division↗

PubMed2006

Tailored strategy for AML patients receiving allogeneic peripheral blood stem cell transplantation.

Considering the heterogeneity of acute myelogenous leukemia (AML), along with the pros and cons of allogeneic peripheral blood stem cell transplantation (PBSCT), a tailored strategy is needed to minimize the transplant-related mortality and maximize the transplant outcomes in AML patients exhibiting certain factors that have an impact on the post-transplant quality of life and outcomes. The factors that need to be considered when tailoring a strategy in an allogeneic PBSCT setting include the recipient's performance status and co-morbid disease include AML risk stratification, disease status, expected severity of graft-versus-host disease, and the necessity of a graft-versus-leukemia effect. Accordingly, this review article describes a possible tailoring strategy for AML patients receiving allogeneic PBSCT based on certain factors influencing the transplant outcome.

Adult↗

PubMed2007

Repetitive cycles of high-dose cytarabine are effective for childhood acute myeloid leukemia: long-term outcome of the children with AML treated on two consecutive trials of Tokyo Children's Cancer Study Group.

BACKGROUND: Various methods of intensive chemotherapy have contributed to an improved survival in pediatric acute myeloid leukemia (AML). We here report the long-term results of the two consecutive trials of Tokyo Children's Cancer Study Group (TCCSG), incorporating repetitive use of high-dose cytarabine (HD-Ara-C) based combination chemotherapy in post-remission phase. PROCEDURE: A total of 216 eligible children with newly diagnosed AML were treated in the two consecutive multi-center trials of TCCSG, M91-13 and M96-14, from August 1991 to September 1998. In M91-13 trial, patients received eight courses of intensive post-remission chemotherapy, including six HD-Ara-C containing courses, after remission-induction therapy. Autologous hematopoietic stem cell transplantation (HSCT) could be selected by physician's choice, and allogeneic HSCT was allocated if donor was available. In M96-14 trial, the last two HD-Ara-C courses were omitted from the chemotherapy arm. RESULTS: The remission-induction rate was 88.8% and probability of 5-year Overall survival (OS) and event-free survival (EFS) were 62% (56-69% with 95% Confidence intervals (CIs)) and 56% (49-62%), respectively. Treatment-related mortality (TRM) was 7.8%. Among patients without Down syndrome (DS) or acute promyelocytic leukemia (APL), the presence of t(8;21) or inv(16) was a significant good prognostic factor both in the univariate and multivariate analyses. Children with DS (N = 10) and APL (N = 14) also showed a good survival exceeding 70% in 5 years. CONCLUSIONS: These results suggest that repetitive use of HD-Ara-C was effective and safe for childhood AML. However, further optimization of AML therapy is required.

Acute Disease↗

PubMed1987

Long-term results of two Swiss AML studies.

The Swiss group for clinical cancer research (SAKK) completed two first line protocols for the treatment of acute myelogenous leukemia (AML). In the first protocol (SAKK AML 74, from August 1974 to April 1977; 107 patients) the effectiveness of immunization with viral oncolysate during maintenance treatment was tested. After successful induction treatment, the patients were randomized in two groups: Group A: monthly maintenance chemotherapy for 2 years and group A+IT, which received the same maintenance chemotherapy regimen plus, on day 15, injection of viral oncolysate. Of the 107 patients, 57 (53%) achieved complete remission, 29 then being randomized to group A, 28 to group A+IT. As of August 1984, there is no statistical difference between the survival times of the two groups (p = 0.288). Ten years after the start of the study there is still no clear plateau of the survival curve. Nine percent of all patients (18% of the remission patients) are alive today. With the treatment of the mid-seventies, therefore, the cure of a patient suffering from AML was a rare event. The second protocol (SAKK AML 77, from April 1977 to April 1982; 162 patients) was designed to evaluate the usefulness of a prolonged maintenance treatment after early consolidation. The 74 patients who were still in remission after early consolidation treatment were assigned to either maintenance chemotherapy or to observation only. At 3.5 years after the last patient's entry there was no difference between the groups in duration of survival (p = 0.332).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Cementless total hip arthroplasty with AML, PCA and HGP prostheses.

Two hundred and fourteen patients who had 270 cementless hip prostheses were followed for 2 to 8 years. PCA (Porous-Coated Monatomic), AML (Monatomic Medullary Locking) and HGP (Harris-Galante-Porous) femoral stems and acetabular cups were used without any preference for the prostheses. The overall clinical results were similar for the three prostheses with average Harris hip scores of 93, 93 and 91 respectively. Four PCA prostheses had radiological aseptic loosening and one was revised because of polyethylene wear. There was no loosening in the AML and HGP prostheses. Pain in the thigh, usually slight, occurred in 17% of AML, 21% of PCA and 19% of HGP prostheses. Five years after operation, radiological changes such as migration, calcar remodelling and radiolucent lines were the same for the 3 prostheses, but bony ingrowth was greater with the AML femoral stems.

Adult↗

PubMed1986

Fibrinogen--proteolysis in acute myelogenous leukemia (AML).

Fibrinopeptides were measured as direct indices of thrombin, plasmin and elastase in plasma samples obtained from patients with AML. Peptide patterns observed were consistent with spontaneous or drug induced plasmin-specific fibrinogenolysis (AML FAB M 1/3), elastase mediated proteolysis (AML FAB M 3/4) or DIC (AML FAB 4/5). DIC was also observed in septic, agranulocytotic patients.

Adult↗

PubMed1993

Chemotherapy for minimally differentiated acute myeloid leukemia (AML-M0). A report on five cases and review of the literature.

With the objective of establishing the optimal therapy for minimally differentiated acute myeloid leukemia (AML-M0), we examined the therapeutic results of five AML-M0 cases and reviewed the literature. In a series of 63 patients with newly diagnosed acute leukemia who were admitted to the Main Hospital of Nippon Medical School, five patients fit the criteria for AML-M0: negative myeloperoxidase (MPO) and Sudan black B reaction by light microscopy, negative for B- and T-lineage markers, and positive for myeloid markers. They were treated by means of AdVP [adriamycin, vincristine, and prednisolone (PSL)] therapy and/or BHAC-DMP [behenoylcytosine arabinoside (BHAC), daunorubicin (DNR), 6-mercaptopurine (6-MP), and PSL] therapy. The AdVP therapy was unsuccessful in the two patients who received it, while a complete remission (CR) was achieved with the BHAC-DMP therapy in three of four patients. Although one patient treated with BHAC-DMP did not achieve CR, his blasts were apparently sensitive to the therapy. In assessable cases in the literature where leukemic blasts were MPO-negative, myeloid marker-positive and B- and T-lineage marker-negative, CR was achieved in 54.5% and 44.4% with anti-acute myeloid leukemia therapy and anti-acute lymphocytic leukemia therapy, respectively. Five cases in the literature were treated with a chemotherapeutic regimen containing BHAC [or cytosine arabinoside (Ara-C)], DNR, and 6-MP, and all achieved CR. The regimen containing BHAC (or Ara-C), DNR, and 6-MP may be useful as induction chemotherapy for AML-M0.

Adult↗

PubMed2026

Defining and managing high-risk acute myeloid leukemia (AML) in 2026.

Acute myeloid leukemia (AML) remains a highly heterogeneous malignancy in which outcomes are particularly poor for patients classified as having high-risk disease. Traditionally, high-risk AML has been defined by adverse baseline genetic features, including complex cytogenetics, TP53 alterations, and mutations associated with secondary or therapy-related disease. However, this static, genetics-centered definition is increasingly insufficient in the modern therapeutic era. Emerging evidence supports a more dynamic and context-dependent model in which risk is shaped not only by molecular architecture but also by treatment intensity, patient fitness, measurable residual disease (MRD), and evolving resistance mechanisms. Advances in genomic profiling have refined risk stratification frameworks, including ELN 2022 for intensively treated patients and the ELN 2024 classification for those receiving less-intensive therapies. In parallel, MRD has emerged as a powerful biomarker that reclassifies patients during treatment, identifying those with persistent, therapy-resistant disease despite morphologic remission. Biologically, high-risk AML is driven by the interplay of clonal evolution, epigenetic plasticity, leukemic stem cell persistence, and protective microenvironmental and immune interactions, all of which contribute to relapse. Therapeutically, the landscape has expanded to include targeted agents, venetoclax-based combinations, and transplantation strategies, yet outcomes remain limited in key high-risk subsets, particularly TP53-mutated disease and post-venetoclax relapse. Accordingly, current strategies emphasize rational combination therapies, MRD-guided treatment adaptation, and approaches targeting both leukemic cells and their supportive niches. In 2026, high-risk AML is best understood as a dynamic, treatment-context-dependent state. Improving outcomes will require integration of precision diagnostics, biologically informed therapy, and adaptive strategies designed to anticipate and overcome resistance.

Humans↗

PubMedDate not supplied

Comparison of karyotype analysis and RT-PCR for AML1/ETO in 204 unselected patients with AML.

The chromosomal translocation t(8;21) (q22;q22) is often associated with acute myeloid leukemia with maturation (AML-M2) and can be detected by a reverse transcription-polymerase chain reaction (RT-PCR) for the AML1/ETO fusion mRNA. We investigated the prevalence of t(8;21) and AML1/ETO in 204 unselected patients with AML and compared the results of cytogenetic analysis with these of RT-PCR. Fifteen of 204 AML patients (7.4%) showed a t(8;21) in karyotype analysis. In 17 of 204 patients (8.3%) AML1/ETO was detected by RT-PCR. All patients who had a t(8;21) in conventional karyotyping also showed the gene rearrangement in molecular analysis, including one patient with a three-way translocation t(5;8;21). AML1/ETO was also detected in two AML patients lacking the t(8;21) cytogenetically. One had a normal diploid karyotype bone marrow (BM) at diagnosis; she has now been in CCR for 12 months. The second patient showed a complex chromosomal anomaly involving chromosome 21, but without a typical 8;21 translocation (BM in relapse). He died in relapse after an overall survival of 60 months. These data indicate that the results of karyotyping and RT-PCR are not completely identical, and molecular biology identifies approximately an additional 5-10% of AML1/ETO positive cases. The clinical relevance of our findings will have to be evaluated with larger patient numbers.

Acute Disease↗

PubMed2002

[Extramedullary initial manifestations of acute myeloid leukemia (AML)].

Extramedullary myeloblastic tumors, so-called myelosarcomas (granulocytic sarcomas, chloromas) have been reported only sporadically in the pertinent literature which reflects their rather infrequent occurrence. These lesions may accompany the initial manifestation or signal relapse of acute myeloid leukemia (AML) or coincide with blastic transformation of a chronic myeloproliferative disorder. However, even more rarely, primary myelosarcomas may precede AML by months or years or may be associated with myelodysplastic syndromes (MDS) that never progress to manifest leukemia. In a retrospective evaluation a clinicopathological study on these latter two variants of isolated extramedullary manifestations of AML was performed to elucidate certain aspects of site involvement and histopathology by application of enzyme and immunohistochemistry. For this reason, we selected 6 patients presenting with a myelosarcoma in combination with MDS and 12 patients revealing only uncharacteristic reactive changes of the bone marrow. Of these patients 8 developed AML following an observation time of up to 2 years. Focal leukemic infiltrates were most often localized in the skin ( n=4), oral mucosa ( n=4), lymph nodes ( n=3), gastrointestinal tract ( n=3) or pleura and retroperitoneum ( n=3 each). Myelosarcomas were usually regarded by the clinicians as putative malignant lymphomas unless further evaluation, especially involving chloroacetate esterase reactions as well as immunostaining with a panel of antibodies reactive with lysozyme, myeloperoxidase, CD68, CD43, CD56, CD117 and CD34 proved their true nature. Although at that time bone marrow findings were inconclusive, a straightforward diagnosis was reached by considering the possibility of a (primary) myelosarcoma in these patients.

Adolescent↗

PubMed1985

NHL-30.5: a monoclonal antibody reactive with an acute myeloid leukemia (AML)-associated antigen.

The reactivity of a murine IgG1 monoclonal antibody, NHL-30.5, that detects a surface antigen expressed on acute myeloid leukemia (AML) cells has been studied. Initially raised against the HL-60 cell line, NHL-30.5 has subsequently reacted with blood and/or bone marrow cells from 15 of 19 AML patients studied at presentation or in relapse, 1 patient with chronic myelomonocytic leukemia (CMML), 1 patient with myelofibrosis (MF) who subsequently developed AML, and 1 of 5 patients with acute lymphoblastic leukemia (ALL). It has shown no detectable binding to cells from AML patients in remission (0/3), patients with chronic myelogenous leukemia in chronic phase (CML) (0/7), normal bone marrow (0/9), normal peripheral blood mononuclear cells, granulocytes, platelets, erythrocytes, monocytes, or splenocytes by radioimmunoassay or fluorescence analysis using flow cytometry. HL-60 cells induced to differentiate following incubation in the presence of dimethylsulfoxide (DMSO) lost their ability to bind NHL-30.5. Immunoprecipitation of iodinated HL-60 cell surface components showed the antigen to have an apparent mol./wt of 180,000 under reducing conditions. These results suggest that the antigen is different from any other myeloid antigens reported to date, and may be useful in further studies of leukemic cell phenotypes.

Adult↗

PubMed1989

New molecular marker in AML: DNA-fingerprint differences between leukemic phase and remission in acute myeloid leukemia.

DNA-fingerprint (DNA-F) analysis, based on the polymorphism of the tandem repeats of minisatellite areas in human genome, has a capacity to reveal minor changes in dispersed areas of human genome. In this study we have applied DNA-F analysis to the detection of differences between leukemic phase and remission in acute myeloid leukemia (AML). In order to identify normal and leukemic cell populations we used two molecular probes: Jeffreys' minisatellite probes 33.6 + 33.15 and M13 wild-type phage probe. Comparison of varying minisatellite fragments between remission and diagnosis/relapse was performed by Southern blot hybridization in 21 patients with AML. The results demonstrate that Southern hybridization with minisatellite probes can detect differences in DNA-fingerprints between leukemic phase and remission in 44% of AML patients. Thus differences in DNA-fingerprinting provides a new molecular marker, which can be useful in the detection of residual disease as well as in the study of the pathogenesis of AML.

Biomarkers, Tumor↗

PubMed1990

Triple combination of retinoic acid + 6-thioguanine + hexamethylene bisacetamide induces differentiation of human AML blasts in primary culture.

Differentiation induction therapy provides an alternative therapeutic approach for patients with acute myeloid leukaemia (AML) who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy. The effect of a triple combination of retinoic acid (RA) + 6-thioguanine (6-Th) + hexamethylene bisacetamide (HMBA) on differentiation of blasts from 24 AML patients was studied. Nonadherent mononuclear cells were seeded at a concentration of 5 x 10(5) cells/ml in 24-well tissue culture plates containing RPMI-1640 culture medium with 20% fetal calf serum and 10% 5637-conditioned medium and incubated with 10(-6) M retinoic acid, 1.5 X 10(-6) M 6-thioguanine and/or 2 mM hexamethylene bisacetamide for six days at 37 degrees C in a humidified incubator under 5% CO2. Morphological, cytochemical and functional differentiation into mature cells were induced in blasts from 22 out of the 24 AML patients following exposure to the triple combination of 10(-6) M RA + 1.5 X 10(-6) M 6-Th + 2 mM HMBA in primary culture. These effective results justify a clinical trial of such triple combination for AML patients who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy.

Acetamides↗

PubMed1990

Susceptibility of acute myeloid leukemia (AML) cells from clinically resistant and sensitive patients to daunomycin (DNR): assessment in vitro after stimulation with colony stimulating factors (CSFs).

Chemosensitivity of purified AML blasts to daunomycin was examined under conditions of CSF stimulation and compared with clinical outcome of DNR combination chemotherapy. AML blasts from 16 patients were purified, incubated serum-free in the presence of optimal concentrations of a complete cocktail of IL-3, GM-CSF and G-CSF to provoke cell proliferation maximally, and DNR drug sensitivity in vitro was assessed by inhibition of DNA synthesis in response to titrated DNR concentrations. The sensitivity of proliferating AML cells to DNR did not correlate with the clinical response of the patients as identical dose-response curves were obtained for complete responders (n = 6), partial responders (n = 5) and resistant cases (n = 5). As a major part of the AML population was induced to enter DNA synthesis in vitro, these data suggest that the manoeuvre of cell cycle stimulation has abrogated cellular resistance to daunomycin and rendered in vivo, apparently refractory cells susceptible to the anthracycline.

Colony-Stimulating Factors↗

PubMed1988

Immunotherapy in acute myelogeneous leukemia (AML)--a tool for maintaining remission?

Twelve trials of adjuvant immunotherapy in patients suffering from AML have been analyzed and compared to results from experimental studies. The analysis presents evidence suggesting that the immune response to leukemia cells exists in a state of balance; this appears to be regulated by the dose of antigen and the state of the cells used to immunize the patients. The injection of high doses of live allogeneic leukemia cells produced a significantly prolonged duration of the first remission in in AML patients. Immunization with high doses of irradiated and dead cells induced some prolongation of the remission phase and survival time, although the percentage of survivors after 3 years was not increased in these groups as compared to non-immunized patients. Immunization by the same route using a 100-fold lower amount of leukemia cells afforded no protection against relapse of the disease during the maintenance phase. A few patients even developed the relapse earlier than did patients treated with chemotherapy alone. Our understanding of the immune responses to malignant cells has increased considerably during the past 2 decades due to various observations. The results obtained with active immunotherapy of the AML patients during the same period agree well with experience from laboratory studies. Thus the results confirm the potential of an immunological interaction between the leukemia cells and the patient. Consequently, it seems likely that the addition of immunotherapy to the treatment of patients with AML might be effective and the tool for maintaining the phase of remission by up-to-date immunological engineering.

Animals↗