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PubMed2004

Lack of KIT or FMS internal tandem duplications but co-expression with ligands in AML.

KIT and FMS, members of the class III receptor tyrosine kinase family, are expressed on normal hematopoietic cells and have important roles in normal hematopoiesis. FLT3 is also a member of the class III receptor tyrosine kinase family and plays important role in hematopoietic stem/progenitor cells, NK, and dendritic cells. Recently, internal tandem duplication (ITDs) mutations have been found in the juxtamembrane (JM) region of FLT3 receptor expressed by patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The mutations result in the constitutive dimerization and activation of the receptor, contributing to leukemic transformation. KIT and FMS are also frequently expressed in AML and are closely related to FLT3. Thus, similar ITD mutations could also occur in the KIT and/or FMS gene of patients with AML. To explore this possibility, 13 human leukemia-lymphoma cell lines and 44 AML patient samples were examined by reverse transcription-polymerase chain reaction (RT-PCR) for the presence of ITD mutations in the JM region of the KIT or FMS receptor. None of the 13 human leukemia-lymphoma cell lines or 44 AML primary bone marrow samples express ITDs in either KIT or FMS in the JM region that is involved in FLT3 mutations. The 13 cell lines and 44 AML samples were also examined for the possible co-expression of KIT and/or FMS receptors with their respective ligands, as we have seen for FLT3 and its ligand, FL. This co-expression could contribute to leukemic transformation through autocrine, paracrine, or intracrine activation mechanisms. And 6/13 cell lines and 27/44 primary AML samples exhibit co-expression of the KIT receptor and ligand (SCF) while 10/13 cell lines and 35/44 primary AML samples exhibit co-expression of the FMS receptor and ligand (CSF-1). Therefore, while ITD mutations were not found, the findings of co-expression of KIT and/or FMS with their respective ligands implies these receptors might contribute to leukemogenesis in some patients with AML through autocrine, paracrine, or intracrine interactive stimulation.

Acute Disease↗

PubMed2002

CD40L induces proliferation, self-renewal, rescue from apoptosis, and production of cytokines by CD40-expressing AML blasts.

OBJECTIVE: Conflicting experimental and clinical results have been reported regarding the role of CD40 in acute myeloid leukemia (AML). In the present study, we analyzed the capability of CD40L/CD154 to modulate several functional aspects of CD40-expressing AML blasts. METHODS: After defining the constitutive expression levels of CD40 in a wide panel (n = 67) of AMLs and evaluating the capability of cytokines to modulate its expression, we investigated the effects of CD40 engagement by soluble (s) CD40L on proliferation, self-renewal capacity, apoptosis, homotypic adhesion, and cytokine production of leukemia cells. RESULTS: CD40 was detected in blast cells from about 37% of AMLs, the highest frequency being documented in monocytic subtypes, and its expression was upregulated or de novo induced by treatment with interleukin (IL)-1alpha, IL-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma, and tumor necrosis factor-alpha. Exposure of CD40(+) AML blasts to sCD40L resulted in a dose-dependent proliferative response, enhancement of clonogenic growth and self-renewal capacity, and a striking increase in colony size. CD40 engagement was able to rescue AML blasts from apoptosis induced by serum deprivation, as demonstrated by reduced expression of APO2.7 and annexin-V binding, as well as upregulation of the anti-apoptotic protein bcl-x(L). CD40 triggering upregulated cell surface expression of the adhesion molecules CD54, CD58, and CD15 and resulted in homotypic aggregation of leukemia cells at least in part CD54-dependent. An increased production of IL-6 and GM-CSF by CD40(+) AML blasts was also documented upon sCD40L exposure. CONCLUSIONS: This study indicates a possible involvement of CD40 in the interactions of AML blasts with other growth-sustaining microenvironmental accessory cells and immune effectors, in turn expressing CD40L. Caution in the use of CD40 triggering in immunotherapy of AMLs is also suggested.

Acute Disease↗

PubMed2003

The inhibitory effect of anti-CD33 monoclonal antibodies on AML cell growth correlates with Syk and/or ZAP-70 expression.

OBJECTIVES: Acute myeloid leukemia (AML) cells express the cell surface antigen CD33 that can function as a downregulator of cell growth, mediating growth arrest and apoptosis. The protein kinase Syk is an essential element in several cascades coupling certain antigen receptors to cell responses. Recently we reported that CD33 recruits Syk for its signaling in AML cell lines. In this study, we further investigated the mechanism(s) of Syk engagement in CD33 signaling in primary AML samples. METHODS: We investigated 25 primary AML samples for their proliferative response (3H-thymidine incorporation) and biochemical changes (Western blot analysis) to anti-CD33 mAb treatment. RESULTS: Proliferation studies demonstrated that 14 (56%) of AML samples were responsive (R) while 11 (44%) were nonresponsive (n-R) to inhibitory antibody activity. Seven of 25 AML samples (28%) expressed undetectable levels of Syk. However, cells from two of these patients expressed the ZAP-70 protein kinase. In Syk/ZAP-70(+) samples, CD33 ligation inhibited proliferation in 70% of cases, while none of the Syk/ZAP-70(-) samples was responsive. There were significant biochemical differences between responder and nonresponder AML populations. In responder samples, CD33 ligation induced phosphorylation of CD33 andSyk and formation of the CD33/Syk complex. In nonresponder samples, CD33 was not phosphorylated, and Syk was in complex with the SHP-1 protein phosphatase constitutively. CONCLUSIONS: Syk is an important component in the regulation of proliferation in AML cells. The differential response of AML cells to CD33 ligation is associated with the level of the Syk expression.

Antibodies, Monoclonal↗

PubMed1996

Down-regulation of bcl-2 in AML blasts by all-trans retinoic acid and its relationship to CD34 antigen expression.

High levels of expression of the bcl-2 oncoprotein in acute myeloblastic leukaemia (AML) cells have been associated with low complete remission rates and poor survival. The sensitivity of AML blasts to drugs such as Ara-C can be increased by the down-regulation of bcl-2 expression by antisense oligonucleotides. All-trans retinoic acid (ATRA) has been reported to increase the sensitivity of AML cell lines to Ara-C and to induce differentiation in the HL60 promyelocytic cell line, with both effects being accompanied by a decrease in bcl-2 expression. Using flow cytometry and a monoclonal antibody to bcl-2, we have investigated the effects of ATRA (1 microM) on bcl-2 expression in the blast cells of 25 AML patients and the K562 cell line after incubation for 72 or 24 h, respectively. Using Kolmogorov-Smirnov statistical analysis where a D value of > 0.12 was statistically significant, we found that in 8/25 AML samples and the K562 cells there was a significant decrease in bcl-2 protein expression after incubation with ATRA (D value range 0.14-0.44). The mean peak fluorescence (MPF) values for the bcl-2 levels of the ATRA responders (n = 8) was reduced to 35.5 +/- 6.9 following incubation with ATRA compared to 47.6 +/- 8.2 (mean +/- SEM) for control samples incubated in the absence of ATRA (P = 0.014). There was no significant difference between the baseline bcl-2 molecules of equivalent soluble fluorochrome (MESF) levels in the ATRA responders (48.9 +/- 5.7, n = 8) and the non-responders (41.3 +/- 3.9, n = 17) (mean +/- SEM) (P = 0.28). The down-regulation of bcl-2 expression by ATRA was particularly associated with CD34-negative AML and of the eight AML patients' cells that responded to ATRA by down-regulating bcl-2, seven were CD34 negative (P < 0.05). Our data suggest that the addition of ATRA to combination chemotherapy would increase the chemosensitivity of some patients with AML, particularly CD34-negative AML, due to down-regulation of bcl-2 expression.

Antigens, CD34↗

PubMedDate not supplied

[Analysis of causes of death during intensive chemotherapy according to treatment protocol AML-BFM 93].

BACKGROUND: During intensive chemotherapy for AML, more than 10% of patients die because of treatment complications but not because of progression of their underlying disease. In order to improve supportive care and to decrease mortality, we analysed the causes of death and their relationship to the cycles of chemotherapy in children undergoing treatment for AML according to the study AML-BFM 93. RESULTS: Thirty-five (7.4%) of a total of 471 patients treated according to protocol AML-BFM 93 died before or within the first 6 weeks after diagnosis (early death). Fourty-nine patients (10%) did not achieve remission, and 18 (4 %) died of therapy-related complications after having achieved remission. In comparison to earlier AML-BFM studies, early mortality was reduced from 13%, 12%, 9% (AML-BFM 78, 83, 87) to 7% (AML-BFM 93, p-trend = 0.03). In contrast, mortality of patients in complete continuous remission (CCR) did not change. Infectious complications, in particular due to bacterial and fungal pathogens, were the main cause of death. One patient died of arrhythmia associated with SIAD. After stem-cell transplantation in first remission, 7 of 51 patients died, mainly because of graft-versus-host-disease and/or infections. The incidence of infectious complications decreased with the number of chemotherapy cycles and was highest during induction therapy. Fatal complications occurred in one patient during maintenance therapy and in one patient thereafter; both patients were in CCR. Another 14 patients died during intensive therapy (before day 150) mostly with a low percentage of blasts, but no haematologic recovery. The cause of death in these children was mainly bacterial infection or invasive aspergillosis, but seldom progression of leukaemia. CONCLUSION: This analysis confirmed the high incidence of fatal infections in children with AML during chemotherapy-induced severe neutropenia. To increase overall survival in children undergoing therapy for AML, we propose (1) to improve the prophylactic and therapeutic measures for haemorrhage and infections, (2) to continue risk-adapted therapy and (3) to treat high-risk patients in specialised centres only.

Adolescent↗

PubMed2002

Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML).

Although many acute myeloid leukemia (AML) colony-forming cells (CFCs) and long-term culture-initiating cells (LTC-ICs) directly isolated from patients are actively cycling, quiescent progenitors are present in most samples. In the current study, (3)H-thymidine ((3)H-Tdr) suicide assays demonstrated that most NOD/SCID mouse leukemia-initiating cells (NOD/SL-ICs) are quiescent in 6 of 7 AML samples. AML cells in G(0), G(1), and S/G(2)+M were isolated from 4 of these samples using Hoechst 33342/pyroninY staining and cell sorting. The progenitor content of each subpopulation was consistent with the (3)H-Tdr suicide results, with NOD/SL-ICs found almost exclusively among G(0) cells while the cycling status of AML CFCs and LTC-ICs was more heterogeneous. Interestingly, after 72 hours in serum-free culture with or without Steel factor (SF), Flt-3 ligand (FL), and interleukin-3 (IL-3), most G(0) AML cells entered active cell cycle (percentage of AML cells remaining in G(0) at 72 hours, 1.2% to 37%, and 0% to 7.6% in cultures without and with growth factors [GFs], respectively) while G(0) cells from normal lineage-depleted bone marrow remained quiescent in the absence of GF. All 4 AML samples showed evidence of autocrine production of 2 or more of SF, FL, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, 3 of 4 samples contained an internal tandem duplication of the FLT3 gene. In summary, quiescent leukemic cells, including NOD/SL-ICs, are present in most AML patients. Their spontaneous entry into active cell cycle in short-term culture might be explained by the deregulated GF signaling present in many AMLs.

Adult↗

PubMed1995

Indirect and direct disruption of transcriptional regulation in cancer: E2F and AML-1.

The disruption of transcriptional regulatory circuits through the elimination of negative regulatory factors (tumor suppressors), the activation of positive acting factors (oncogenes), or when chimeric proteins result from chromosomal translocations, is likely a key event in multistep tumorigenesis. Here, using the transcription factors E2F and AML-1 as model systems, we discuss the disruption of coordinate transcriptional regulation in oncogenesis. E2F oncogenic signals are released when the pRb tumor suppressor is inactivated, and E2F activation may necessitate the coordinate inactivation of a second tumor suppressor, p53. AML-1 is the target of the (8;21) translocation, found in approximately 15% of acute myeloid leukemia (AML) cases, and the t(12;21), found in up to 30% of childhood B-cell acute lymphoblastic leukemias. The t(8;21) creates a fusion protein between AML-1 and a gene of unknown function, mtg8 (ETO), whereas the t(12;21) fuses the TEL (translocation-ets-leukemia) transcription factor to the N-terminus of AML-1. The inv(16), which is the most frequent anomaly found in AML, also targets AML-1, by fusing the gene that encodes AML-1's heterodimeric partner CBF beta to the smooth muscle myosin heavy chain gene MYHll. Thus, E2F and AML-1 provide excellent models for the disruption of transcriptional regulation in cancer.

Carrier Proteins↗

PubMed1995

Clinical, morphologic, cytogenetic and prognostic implications of CD34 expression in childhood and adult de novo AML.

Expression of CD34 by leukemic blasts was analyzed in 230 pediatric and 251 adult patients with de novo AML enrolled in two large multicenter trials (AML-BFM-87 and AMLCG respectively). The association between CD34 positivity and morphological classification according to FAB criteria, cytogenetic aberrations, immunophenotypic features and clinical characteristics was investigated. CD34 was expressed (> or = 20%) by leukemic cells from 45% of childhood and 43% of adult AML patients. CD34+ AML was often associated with M1/M2 morphology as well as the coexpression of CD7 and TdT. Translocation t(8;21), inv(16) and chromosome 5 and 7 aberrations were more frequently observed in CD34+ AML. There was a low frequency of CD34 expression in infant AML but no age dependency was evident in adult patients. CD34 expression exerted no influence on the rate of complete remissions (CR) after intensive multidrug induction therapy. In adults, 56% of the CD34-positive and 64% of CD34-negative cases achieved CR (P = 0.29), and the childhood trial even revealed a slight advantage for CD34+ AML with a CR rate of 80% vs. 71% for CD34-negative cases (P = 0.068). Long-term follow-up disclosed no significant differences in remission duration or event-free survival between the CD34-positive and CD34-negative groups. In conclusion, CD34+ AML patients comprise a heterogeneous group with good as well as poor risk factors. Though characterized by some distinct features, CD34 lacks prognostic significance in de novo AML patients submitted to intensive polychemotherapy.

Adolescent↗

PubMed1979

Suppression of lymphoproliferative responses to alloantigens by autologous AML cells.

Autologous acute myeloid leukaemia (AML), cells caused the suppression of incorporation of 3H-thymidine (3H-Tdr) by remission lymphocytes stimulated with allogeneic cells. In five patients, autologous AML cells suppressed 3H-Tdr uptake by lymphocytes stimulated with up to three different allogeneic cells. Responses to allogeneic AML cells were more strongly suppressed than responses to pooled allogeneic lymphocytes. Suppression was abolished by ultrasonic disintegration of the autologous AML cells, suggesting that a soluble factor was not involved. Suppression was absent from autologous AML cells exposed to ultraviolet light, or when untreated autologous AML cells were present in ratios of less than 1:1 to lymphocytes, or when added 24 or more hours after stimulation of remission lymphocytes with allogeneic cells. It is suggested that suppression is a property of the differentiative level of AML cells, rather than of their malignant properties, although malignant-transformation may bring AML cells into contact with circulating T cells in vivo. Autologous AML cells seem to interfere with the recognition phase of T cell function.

Cell Division↗

PubMed1990

Clinical and roentgenographic evaluation of noncemented porous-coated anatomic medullary locking (AML) and porous-coated anatomic (PCA) total hip arthroplasties.

Eighty-four primary noncemented porous-coated total hip arthroplasties (THAs) in 78 patients were reviewed clinically and roentgenographically at an average follow-up period of 37 months. The average patient age was 51.9 years. Sixty-four Anatomic Medullary Locking (AML) devices were placed in 58 patients, and 20 Porous-Coated Anatomic (PCA) devices were placed in 20 patients. The AML devices had been in situ an average of 36 months (range, 24-49 months), and the PCA devices had been in situ an average of 40 months (range, 29-51 months). The average patient ages were 52.7 and 49.2 years for AML and PCA patients, respectively. The AML devices included three that were fully coated, 59 that were five-eighths coated, and two that were one-third coated. The average preoperative Harris hip score was 38.2 for the AML devices and 33.2 for the PCA devices. The average postoperative Harris hip score was 80.7 for the AML devices and 83.8 for the PCA devices. Pain related to the implant was present in 30% of the AML devices and 30% of the PCA devices. Roentgenographically, no component demonstrated complete radiolucency, and all components demonstrated roentgenographic evidence of bone ingrowth. Roentgenographic changes with time noted for both the AML and PCA devices included: neck roundoff, neck osteolysis, neck corticocancellization, endosteal bone bridging, and distal hypertrophy. On roentgenographic zonal analysis, radiolucency greater than 1 mm was observed most frequently in the most proximal lateral zone and distal tip of the femoral component. The current series of cases, although clinically acceptable, does not support the current widespread enthusiasm for primary noncemented AML and PCA total hip systems. Cemented THA appears to produce superior clinical results, particularly when contemporary cementing techniques are employed.

Adult↗

PubMed1988

Distribution of the 124-kd antigen defined by monoclonal antibody AML-1-99 on normal and leukemic myeloid cells.

We have produced a monoclonal antibody (MoAb), AML-1-99, that defines a novel 124-kd protein antigen expressed on a subpopulation of monocytes and on the majority of hematopoietic progenitor cells of the granulocyte-monocyte (CFU-GM), erythroid, and mixed-lineage classes. AML-1-99 is lytic to bone marrow (BM)- and peripheral blood-derived progenitor cells in the presence of rabbit complement (C'). AML-1-99 is not toxic to progenitor cells in the absence of C', nor does it modify their growth when included in colony-forming cultures. Several leukemia cell lines, including HL-60, U937, KG-1a, and Daudi cells, express the antigen on the majority of cells. Freshly isolated leukemia cells from patients with acute myelogenous leukemia (AML) react variably with AML-1-99. Leukemia colony-forming cells from several AML patients express the antigen and could be eliminated by treatment with AML-1-99 and C'. Cell sorting and immune rosette techniques were successfully applied to normal BM and chronic myelocytic leukemia cell populations using AML-1-99 with the result that significant enrichment of CFU-GM could be accomplished. The pattern of reactivity of this MoAb and its apparent molecular weight suggests that AML-1-99 recognizes a newly defined myeloid-associated cell surface antigen.

Antibodies, Monoclonal↗

PubMedDate not supplied

Low-dose cytosine arabinoside (LD-Ara C) treatment in dysmyelopoietic syndromes (DMPS) and acute myelogenous leukemia (AML).

The effect of low-dose Ara C (LD-Ara C) (10 mg/m2 q 12 hr s.c.) for a minimum of 10 days was evaluated in 21 patients with acute myeloid leukemia (AML) and 15 patients with dysmyelopoietic syndromes (DMPS). Median age (range) for AML-patients was 47 yrs (19-89), and for DMPS-patients 60 (22-78). From the AML-group, 9 patients were either primary refractory or resistant to intensive re-induction treatment of relapse, 6 others had heavy pretreatment, 1 suffered from myelosclerosis. Five AML-patients had no pretreatment at first presentation and were started on LD-Ara C because of old age (3) or poor condition (2) including 1 patient with a secondary leukemia. DMPS included those with RAEB (8) and RAEB in transformation (7). 12 patients with AML and 4 with DMPS displayed a leukocytosis of greater than 10 X 10(9)/l. Three out of 21 AML-patients reached complete remission (CR), one of them twice, with partial remission (PR) at the third attempt with this type of treatment. Two other AML-patients reached a P.R. of 5 and 1 months duration respectively. Three patients experienced a transient response characterized by improved peripheral blood counts and cessation of transfusion requirements, one of them for 12 months. In 5 AML-patients no effect was seen and 8 pts. died. In the DMPS-group, 5/15 patients reached C.R., one patient twice with the same treatment, 1 patient reached a P.R., 1 improved, 6 showed no effect, and 2 died. In 13 patients final examination of the bone marrow was not performed after treatment because of either early death or obvious progression. Treatment was associated with significant, transient hematologic toxicity. Patients suffering from DMPS had prolonged aplasia and required more blood and platelet support than pts with AML. Responding leukemia patients had a rapid hematologic regeneration. Considering the poor prognosis of both of our treatment groups, this therapeutic approach proved to be of considerable benefit.

Adult↗

PubMed1999

Molecular mapping of chromosome 2 deletions in murine radiation-induced AML localizes a putative tumor suppressor gene to a 1.0 cM region homologous to human chromosome segment 11p11-12.

Radiation-induced acute myeloid leukemias (AMLs) in the mouse are characterized by chromosome 2 deletions. Previous studies showed that a minimal deleted region (mdr) of approximately 6.5 cM is lost from one homologue in chromosome 2-deleted AMLs. An AML tumor suppressor gene is proposed to map within this mdr. In this study, we refine the mdr to a I cM interval between markers D2Mit126 and D2Mit185 by microsatellite analysis of 21 primary radiation-induced F I AMLs. The construction of a partial yeast artificial chromosome (YAC) contig spanning the mdr and the location of six known genes indicated that the 1 cM mdr is homologous to human 11p11-12, a region implicated in some human AMLs. Screening of five cell lines derived from primary radiation-induced AMLs for homozygous loss of microsatellites and genes mapping within the mdr revealed loss of both copies of the hemopoietic tissue-specific transcription factor Sfpi1(PU.1/Spi1) in one cell line. Studies of primary and F1 AMLs failed to implicate Sfpi1 as the AML tumor suppressor gene. YAC contig construction, together with data suggesting that the critical gene flanks Sfpi1, represents significant progress toward identifying an AML tumor suppressor gene.

Animals↗

PubMed2007

Inhibition of Flt3-activating mutations does not prevent constitutive activation of ERK/Akt/STAT pathways in some AML cells: a possible cause for the limited effectiveness of monotherapy with small-molecule inhibitors.

The Flt3 receptor tyrosine kinase is a critical mediator in the pathogenesis of acute myeloid leukaemia (AML). Flt3-activating mutations have been associated with poor prognosis and decreased overall survival of AML patients, thus Flt3 constitutes an ideal target for drug treatment of such disease. Unfortunately, the monotherapy with small-molecule tyrosine kinase inhibitors in clinical trials shows that remission is not permanent, presumably by resistance of Flt3 mutants to inhibitors. An alternative approach for treatment is based on the cooperation between Flt3 and additional intracellular pathways for AML transformation in some patients. Thus, the inhibition of both Flt3 and such pathways may be exploited for successful treatment of the disease. We investigated the importance of Flt3-activating mutations for the constitutive activation of intracellular pathways in primary AML cells, and their effect on cell survival. We found that the main compounds involved in the differentiation, proliferation and survival of AML (MAPK/AKT/STAT) were constitutively activated. However, only four samples showed internal tandem duplications (ITDs) for Flt3. Surprisingly, contrary to previous reports, we found that inhibition of ITD/Flt3 activity did not prevent the phosphorylation of ERK, STAT5 or Akt in some primary AML cells. In parallel, we found that in these cells, Flt3 and ERK or Akt cooperate to regulate cell survival. Our results support the hypothesis that the optimal therapeutic treatment of AML may require not only the oncogenic tyrosine kinase, but also the appropriate combination of different specific inhibitors, thus providing a more effective approach to reverse leukaemogenesis. Thus, we propose that each AML patient should have an individually tailored combination treatment.

Acute Disease↗

PubMed2026

KIT and FLT3-ITD mutations do not predict outcomes in pediatric core-binding factor acute myeloid leukemia: findings from the C-HUANAN-AML-15 multicenter cohort study.

Although core-binding factor acute myeloid leukemia (CBF-AML) is generally considered a favorable-risk subtype in children, disease relapse remains a significant concern. The prognostic relevance of co-occurring mutations, particularly KIT and FLT3-ITD, remains debatable, and treatment intensity may modulate their impact. This multicenter analysis included 289 children (< 14 years) with newly diagnosed CBF-AML enrolled in the C-HUANAN-AML-15 study (2015-2023). KIT and FLT3-ITD mutations were identified via cytogenetic analysis and targeted sequencing. Measurable residual disease (MRD) was evaluated by multiparameter flow cytometry (MFC) and quantitative polymerase chain reaction (PCR) following induction chemotherapy. Survival analyses were performed using Kaplan-Meier and Cox regression methods. This multicenter analysis included 289 children (< 14 years) with newly diagnosed CBF-AML enrolled in the C-HUANAN-AML-15 study (2015-2023). KIT and FLT3-ITD mutations were identified via cytogenetic analysis and targeted sequencing. Measurable residual disease (MRD) was evaluated by multiparameter flow cytometry (MFC) and quantitative polymerase chain reaction (PCR) following induction chemotherapy. Survival analyses were performed using Kaplan-Meier and Cox regression methods. KIT mutations were detected in 103 patients (35.6%), predominantly involving exon 17 (69.9%), and were associated with extramedullary disease, sex chromosome loss, and trisomy 22. No significant differences in 5-year event-free survival (EFS), overall survival (OS), or cumulative incidence of relapse (CIR) were observed between patients with and without KIT mutations. FLT3-ITD mutations (5.5% of patients) did not adversely affect outcomes. Neither mutation independently predicted survival. MRD positivity (MFC-MRD ≥ 0.1%) after the second induction cycle strongly predicted inferior EFS and OS and higher CIR, with corresponding results observed for molecular MRD and parallel findings for PCR-based MRD. In this large multicenter cohort, KIT and FLT3-ITD mutations did not adversely affect the prognosis of pediatric CBF-AML treated according to the C-HUANAN-AML-15 protocol. MRD after induction was the most powerful predictor of relapse and survival, underscoring its importance for risk stratification in future pediatric AML trials.

Humans↗

PubMed1990

GM-CSF incubation prior to treatment with cytarabine or doxorubicin enhances drug activity against AML cells in vitro: a model for leukemia chemotherapy.

We studied the effect of preincubation with recombinant GM-CSF on the activity of cytarabine and doxorubicin against clonogenic acute myeloid leukemia cells (CFU-AML). Leukemia cells from seven persons with AML, three myeloid cell lines (HL60, KG1, K562) and two control cell lines (U937, MOLT3) were tested. Preincubation with GM-CSF (0.01-0.1 microgram/ml) increased DNA synthesis as measured by tritiated thymidine incorporation and intranuclear Ki67 expression in cells from six persons with AML and in HL60 cells. Leukemia cells preincubated with GM-CSF for 6-48 h were exposed to cytarabine (2-200 micrograms/ml) or doxorubicin (0.01-0.1 microgram/ml) for 3 h and CFU-AML assayed. This approach further reduced CFU-AML in samples from six persons with AML and in HL60 and KG1 cells compared to cells not preincubated with GM-CSF prior to drug treatment. In most instances, reduced CFU-AML correlated with GM-CSF induced DNA synthesis. These data suggest a possible strategy of GM-CSF pretreatment to increase anti-leukemia efficacy of chemotherapy in AML.

Cytarabine↗

PubMed1997

Long-term survival and development of secondary malignancies in patients with acute myeloid leukemia treated with aclarubicin or daunorubicin plus cytosine arabinoside followed by intensive consolidation chemotherapy in a Danish national phase III trial. Danish Society of Haematology Study Group on AML.

In 1991 we reported the results from a prospective randomised phase 3 trial comparing 7 days continuous infusion of cytosine arabinoside (ara-C) combined with either daunorubicin (DNR) or aclarubicin (ACR) as direct i.v. injection for 3 days as induction chemotherapy (CT) for patients with de novo acute myeloid leukemia (AML) followed by early intensive consolidation CT with two alternating cycles of high-dose ara-C and two cycles of amsacrine plus etoposide, and finally 3 days of daunomycin plus 7 days of ara-C as administered for induction of remission. A total of 174 patients with de novo AML in the age group 17-65 years were included. The patients have now been followed till death or for at least 7 years, and an evaluation of the long-term survival and the risk of developing secondary neoplasms has been made. The overall survival rate 5-years after diagnosis was 23%, and after 10 years 19%. No difference was found between the two treatment regimens in overall survival or disease-free survival (DFS). For the subgroup of 99 patients who achieved complete remission after one or two induction courses, 5- and 10-year survival rates were 35% and 31% respectively, with the highest survival rates in the age group 17-39 years (57% at 5 years) as compared with 27% in patients aged 40-60 years (P= 0.007). Seven secondary neoplasms were diagnosed simultaneously with or after the diagnosis of AML indicating a standardized incidence ratio (SIR) of 3.41, (95% CI: 1.60-7.26). In three cases the secondary neoplasms were diagnosed simultaneously with the AML diagnosis and were for that reason completely unrelated to the chemotherapy administered for AML, as the psammomatous meningeoma diagnosed after only 8 months. The remaining three neoplasms which developed subsequently did not significantly exceed the expected number, with a SIR = 1.46 (0.47-4.57). Thus, no increased risk of solid tumors causally related to the intensive chemotherapy for de novo AML was observed. However, a generally increased risk of solid tumors in patients diagnosed simultaneously with the AML diagnosis seems likely. Over 20% of the patients were alive and in complete remission 5 years after the AML diagnosis, and they have a high probability of surviving the next 5-year period.

Aclarubicin↗

PubMed1997

Differential effect of GM-CSF pretreatment on intracellular Ara-C metabolism in normal bone marrow mononuclear cells vs acute myeloid leukemia (AML) blasts.

The effect of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) on the intracellular metabolism of cytosine arabinoside (Ara-C) was comparatively analyzed in normal bone marrow mononuclear cells (NBMMC) from eight healthy volunteers and in leukemic blasts from 50 patients with acute myeloid leukemia (AML). Pretreatment with GM-CSF (100 U/ml) for 48 h resulted in a significant enhancement of DNA synthesis in both cell types: 21 of 35 AML specimens were found to be responsive to GM-CSF as defined by an increase of 3H-TdR incorporation into the DNA > 1.5-fold while NBMMC from normal donors were responsive in all cases. In GM-CSF responsive AML blasts, overall DNA polymerase and DNA polymerase alpha activity increased from a median of 84.4 to 96.1 and from 3.45 to 5.2 pmol/min x mg as compared to a median of 96.7 to 189.9 and 1.2 to 2.2 pmol/min x mg in NBMMC (P < 0.05). Median Ara-C-mediated inhibition of DNA synthesis was significantly more effective in AML blasts as compared to NBMMC (76.5 vs 55.0% at 0.05 microM and 99.0 vs 96.0% at 5.0 microM Ara-C, P < 0.01) but was not influenced by GM-CSF pretreatment. Similarly, intracellular Ara-CTP levels were higher in AML blasts as compared to NBMMC (median of 46.9 vs 18.7 at 1 microM, 167.8 vs 48.0 at 10 microM and 337.5 vs 59.5 ng/10(7) cells at 100 microM extracellular Ara-C, P < 0.01) but showed no enhancement in the presence of GM-CSF. Median deoxycytidine (DCK) and thymidine kinase (TK) activity were only slightly increased in AML blasts after GM-CSF priming. In contrast, NBMMC revealed a significant increase in TK activity after GM-CSF pretreatment (from a median of 1.9 to 3.6 pmol/min x mg, P = 0.039). At low; intermediate and high extracellular Ara-C concentrations GM-CSF pretreatment resulted in a significant enhancement of the 3H-Ara-C incorporation into the DNA in both GM-CSF responsive AML blasts and NBMMC (median of 1.3 to 2.1- and 1.4 to 1.6-fold, P < 0.05). GM-CSF non-responsive AML blasts showed no change in 3H-Ara-C incorporation into the DNA in response to GM-CSF at low Ara-C concentrations but significant increases at intermediate and high extracellular Ara-C concentrations (median increases of 1.63-fold at 1.06 microM with P = 0.01 and 1.37-fold at 10 microM extracellular Ara-C with P = 0.0+005). NBMMC revealed significantly lower GM-CSF-induced increases of the 3H-Ara-C incorporation into the DNA as compared to the effect of GM-CSF priming on DNA synthesis (median increases of 1.4 to 1.7-fold vs 2.6-fold, P < 0.05). These data reveal a different effect of GM-CSF priming on the metabolism of Ara-C in normal vs leukemic cells which may cause a preferential increase in the antileukemic cytotoxicity of Ara-C in the presence of GM-CSF.

Adult↗