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Acute Myeloid Leukemia
... In this disease, the bone marrow is infiltrated by these immature cells, known as blasts, hindering the production of other vital blood components like red blood cells and platelets. This disruption results in complications such as anemia, susceptibility to infections, and unusual bleeding tendencies [1]. AML prognosis is 5%À15% in aging (more than 65 years) patients [2,3]. ...
... Among them, nine (30%) attained molecular remission (MR), with responders exhibiting significantly higher 5year OS compared to non-responders (53.8% vs. 25.0%). Additionally, Stimulation of PR [9] " CD4 + and CD8 + T cells [21] " TH1 cytokines [21] Feeling cold [8], Myalgia [5], Fever [7] Van Tendeloo et al. (2012) 10 Induction of CR [2] Induction of CMR [5] Median OS time (22.2 mo) " WT1-specific T cells [5] NK activation Positive DTH [10] Redness and hardening at the injection site [10], pain at the level of the draining axillary lymph nodes [1], platelet count dropped [1], gentle flare-up of an ongoing Achilles and foot tendon annoyance [ "WT1-specific T cells [2] "PRAME-specific T cells [4] "CMVpp65-specific T cells [9] Transient vaccine site reactions (erythema, induration, pruritus) [10], musculoskeletal pain [6], skin reactions, outside of vaccine sites [5], diarrhea [4], fatigue [4] Kitawakia et al. 17 Induction of CR [12] Favorable RFS (71% at 57 m) " AML-reactive T cells [6] " AML Ag-specific T cells [2] (i.e., MUC1, WT1 or PRAME) [52] evaluated DCs loaded with RNA containing AML-associated antigens (WT1 and PRAME) along with CMVpp65, demonstrating a median recurrence-free survival of 36.1 months. ...
... Among them, nine (30%) attained molecular remission (MR), with responders exhibiting significantly higher 5year OS compared to non-responders (53.8% vs. 25.0%). Additionally, Stimulation of PR [9] " CD4 + and CD8 + T cells [21] " TH1 cytokines [21] Feeling cold [8], Myalgia [5], Fever [7] Van Tendeloo et al. (2012) 10 Induction of CR [2] Induction of CMR [5] Median OS time (22.2 mo) " WT1-specific T cells [5] NK activation Positive DTH [10] Redness and hardening at the injection site [10], pain at the level of the draining axillary lymph nodes [1], platelet count dropped [1], gentle flare-up of an ongoing Achilles and foot tendon annoyance [ "WT1-specific T cells [2] "PRAME-specific T cells [4] "CMVpp65-specific T cells [9] Transient vaccine site reactions (erythema, induration, pruritus) [10], musculoskeletal pain [6], skin reactions, outside of vaccine sites [5], diarrhea [4], fatigue [4] Kitawakia et al. 17 Induction of CR [12] Favorable RFS (71% at 57 m) " AML-reactive T cells [6] " AML Ag-specific T cells [2] (i.e., MUC1, WT1 or PRAME) [52] evaluated DCs loaded with RNA containing AML-associated antigens (WT1 and PRAME) along with CMVpp65, demonstrating a median recurrence-free survival of 36.1 months. ...
... Acute myeloid leukemia (AML) is the most common form of acute leukemia in children and adults with genetic, epigenetic, and phenotypic heterogeneity [1,2]. Sequential treatment with Cytarabine and daunorubicin/idarubicin remains to be the standard induction protocol in AML treatment. ...
... AML is the most common form of acute leukemia, characterized by the accumulation of malignant myeloid precursor cells, and called as a stem cell disease due to the arrest in the differentiation phase in the bone marrow [1,2]. Cytarabine and DNR or idarubicin (anthracycline agents) are still used as the standard treatment in AML. ...
Acute myeloid leukemia (AML) is a form of acute leukemia with the highest incidence and the lowest overall survival rates. Insufficiency of targeting leukemia stem cells (LSC) is the main obstacle that causes drug resistance and relapse in AML. Another important problem is chemotherapeutics’ toxicity. Developing a combination, including well-known chemotherapeutics in lower dose and new agent that have capacity to target LSC may be more reliable and practical way to overcome these limitations. Previously, we found that Casticin polyphenol induces apoptosis in AML stem-like (KG1a) and parental (KG1) cell lines without affecting healthy cell. Therefore, for the first time, we aimed to find synergistic combination of Daunorubicin (DNR) and Casticin to target apoptosis in both LSC and leukemic blasts with less toxicity. Synergism of DNR-Casticin combinations on KG1a, KG1, HL-60 cells were determined with MTT viability assay by Chou-Talalay method. The apoptotic/necrotic effects of combinations were evaluated with Annexin V- PI kit by flow cytometry. Synergistic combination of 0.25 µM DNR + 0.0625 µM Casticin (combination index, CI<1) decreased cell viability to 45.3% and 63.2% in KG1a, KG1 cell lines, respectively. However, the combination-induced apoptosis (KG1a: 5 %; KG1: 5.8%) were not higher than 0.25 µM DNR-induced (KG1a: 9.4%; KG1: 8.1%) or 0.0625 µM Casticin-induced (KG1a: 3.8%; KG1: 5.1%) apoptosis (p>0.05). Our study showed that synergistic combination of DNR-Casticin causes important decrease in cell viability. Although we did not detect increase in apoptosis with the combination, we presume that other cell death pathways may be included. The highest apoptosis was obtained by the treatment of 2 µM Casticin alone in KG1a (21.7%), KG1 (26.5%), HL-60 (14.6%). Therefore, we think that Casticin polyphenol might be the possible candidate for new targeted therapy studies for AML.
... Additionally, the molecular heterogeneity found within AML patients can lead to varying treatment outcomes [4][5][6] . Therefore, it is essential to identify molecular markers at the time of diagnosis to predict the risk of treatment failure or relapse and survival outcomes of AML patients [7] . ...
Given the extremely high inter-patient heterogeneity among acute myeloid leukemia (AML), identifying biomarkers for prognostic assessment and therapeutic guidance is crucial. Cell surface markers (CSMs) have been shown to play an important role in AML leukemogenesis and progression. In this study, we evaluate the prognostic potential of all human CSMs in AML patients based on differential gene expression analysis and univariate Cox regression analysis. Utilizing multi-model analysis, including Adaptive LASSO regression, LASSO regression, and Elastic Net, we construct a 9-CSMs prognostic model for risk stratification of AML patients. The predictive value of the 9-CSMs risk score is further confirmed in three independent datasets. Multivariate Cox regression analysis shows that the risk score is an independent prognostic factor for AML patients. AML patients with high 9-CSMs risk scores have shorter overall and event-free survival time than those with lower scores. Notably, our single-cell RNA-seq analysis indicates that patients with high 9-CSMs risk scores exhibit chemotherapy resistance. Further, PI3K inhibitors are identified as potential treatments for these high-risk patients. In conclusion, we construct a 9-CSMs prognostic model which is an independent prognostic factor for the survival of AML patients and has the potential to guide drug therapy.
... Leukemia is an infrequent hematological disease characterized by abnormal cell growth and the progression of leukocytes and their precursors in the blood and bone marrow (Downing et al., 1999). Leukemia is the 10 th most familiar cancer in men and 12 th most common in women and constitutes 3% of the global cancer burden (Parkin et al., 1993). ...
L-asparaginase was screened for during the current study in several Caryota urens plant sections. One possible source for L-asparaginase synthesis was identified as the unripe fruit with the highest enzyme activity (925U/ml). The discovery of L-asparaginase in Caryota urens is a first. The enzyme was 38% pure, with an 85-fold purification factor, and 3325U/ml of total enzyme activity after purification. It was discovered that the enzyme's kinetic parameters, Km and Vmax, were 13.8 mM and 100μM/ml, respectively. The partly purified enzyme was shown to be a single protein with a molecular weight of 47 kDa by SDS-PAGE electrophoresis. The cytotoxic effects of L-asparaginase against the K562 and PBMC (peripheral blood mononuclear cell) cell line were investigated; the results showed 26% and 96% (IC50 23.03μg/ml) of cytotoxicity, respectively. Future research can examine the effectiveness of L-asparaginase from Caryota urens L., as it exhibits little glutaminase activity and reduced toxicity toward PBMC.
... Acute myeloid leukaemia (AML) is a malignant haematological disease characterised by impaired myeloid differentiation and abnormal proliferation of haematopoietic stem cells (HSCs). 1 It is the most common type of adult leukaemia with a median age at diagnosis of 68 years. 2 Intensive chemotherapy followed by consolidation chemotherapy and HSC transplantation is the major treatment. Additionally, the emerging targeted therapies show promising prospects. ...
Background
Acute myeloid leukaemia (AML) is a haematological malignancy with unfavourable prognosis. Despite the effectiveness of chemotherapy and targeted therapy, relapse or drug resistance remains a major threat to AML patients. N6‐methyladenosine (m ⁶ A) RNA methylation and super‐enhancers (SEs) are extensively involved in the leukaemogenesis of AML. However, the potential relationship between m ⁶ A and SEs in AML has not been elaborated.
Methods
Chromatin immunoprecipitation (ChIP) sequencing data from Gene Expression Omnibus (GEO) cohort were analysed to search SE‐related genes. The mechanisms of m ⁶ A‐binding proteins IGF2BP2 and IGF2BP3 on DDX21 were explored via methylated RNA immunoprecipitation (MeRIP) assays, RNA immunoprecipitation (RIP) assays and luciferase reporter assays. Then we elucidated the roles of DDX21 in AML through functional assays in vitro and in vivo. Finally, co‐immunoprecipitation (Co‐IP) assays, RNA sequencing and ChIP assays were performed to investigate the downstream mechanisms of DDX21.
Results
We identified two SE‐associated transcripts IGF2BP2 and IGF2BP3 in AML. High enrichment of H3K27ac, H3K4me1 and BRD4 was observed in IGF2BP2 and IGF2BP3, whose expression were driven by SE machinery. Then IGF2BP2 and IGF2BP3 enhanced the stability of DDX21 mRNA in an m ⁶ A‐dependent manner. DDX21 was highly expressed in AML patients, which indicated a poor survival. Functionally, knockdown of DDX21 inhibited cell proliferation, promoted cell apoptosis and led to cell cycle arrest. Mechanistically, DDX21 recruited transcription factor YBX1 to cooperatively trigger ULK1 expression. Moreover, silencing of ULK1 could reverse the promoting effects of DDX21 overexpression in AML cells.
Conclusions
Dysregulation of SE‐IGF2BP2/IGF2BP3‐DDX21 axis facilitated the progression of AML. Our findings provide new insights into the link between SEs and m ⁶ A modification, elucidate the regulatory mechanisms of IGF2BP2 and IGF2BP3 on DDX21, and reveal the underlying roles of DDX21 in AML.
... The quantities and proportions of these cells serve as crucial indicators for assessing health status. For instance, an abnormal WBC count can indicate infections, inflammation, immune system issues, or severe conditions such as leukemia [6]. Changes in RBC counts are frequently associated with anemia [7], stemming from deficiencies in iron, folate, or vitamin B12 or due to chronic diseases and bone marrow problems. ...
In the field of biomedical science, blood cell detection in microscopic images is crucial for aiding physicians in diagnosing blood-related diseases and plays a pivotal role in advancing medicine toward more precise and efficient treatment directions. Addressing the time-consuming and error-prone issues of traditional manual detection methods, as well as the challenge existing blood cell detection technologies face in meeting both high accuracy and real-time requirements, this study proposes a lightweight blood cell detection model based on YOLOv8n, named GPMB-YOLO. This model utilizes advanced lightweight strategies and PGhostC2f design, effectively reducing model complexity and enhancing detection speed. The integration of the simple parameter-free attention mechanism (SimAM) significantly enhances the model’s feature extraction ability. Furthermore, we have designed a multidimensional attention-enhanced bidirectional feature pyramid network structure, MCA-BiFPN, optimizing the effect of multi-scale feature fusion. And use genetic algorithms for hyperparameter optimization, further improving detection accuracy. Experimental results validate the effectiveness of the GPMB-YOLO model, which realized a 3.2% increase in mean Average Precision (mAP) compared to the baseline YOLOv8n model and a marked reduction in model complexity. Furthermore, we have developed a blood cell detection system and deployed the model for application. This study serves as a valuable reference for the efficient detection of blood cells in medical images.
... AML is a heterogenous hematological malignancy of the stem cell precursors of the myeloid lineage (Löwenberg et al., 1999). Enzymatic function of MTHFD2 sustains rapid cell proliferation during early embryogenesis, while transforming to MTHFD2L in mature cells. ...
One-carbon metabolism is a universal metabolic process that mediates the transfer of one-carbon units for purine and thymidine synthesis. One-carbon metabolism has been found to be dysregulated in various cancer types due to its role in production of purine and pyrimidine nucleotides, epigenetic program, and redox homeostasis. One-carbon metabolism is composed a network of one-carbon metabolic enzymes. Disturbing the expression and enzymatic activity of these one-carbon metabolic enzymes could lead to fluctuations of metabolites in the tumor microenvironment. Serine hydroxymethyltransferases (SHMTs) and methylenetetrahydrofolate dehydrogenases (MTHFDs) are gradually recognized as important one-carbon metabolic enzymes for regulating tumor initiation and development, representing potential therapeutic targets for anti-tumor strategies. In the review, we primarily focused on the role of SHMTs and MTHFDs in cancer. Several inhibitors targeting MTHFDs and SHMTs have exert its potential to decrease tumor burden and inhibit tumor proliferation, highlighting the potential of targeting one-carbon metabolic enzymes for anti-cancer strategies.
... AML is characterized by an increase in the number of myeloid cells in the bone marrow and a disruption in their maturation process. This condition typically leads to insufficient blood cell production, low levels of granulocytes and platelets, and anemia, sometimes accompanied by high white blood cell counts (Lowenberg et al., 1999). The primary treatments for AML consist of chemotherapy, radiotherapy, and hematopoietic stem cell transplantation (HSCT). ...
Leukemia is a type of cancer that affects the lymphatic system and bone marrow. It is a heterogeneous disorder with two main types: acute and chronic leukemia. Acute leukemia is more aggressive and severe in children, whereas chronic leukemia mainly affects adults and is comparatively less aggressive. If left untreated, both types can lead to serious illness and even death. Although there are treatment options available such as chemotherapy, radiation therapy, immunotherapy, and the popular CART therapy, leukemia remains a challenging disease worldwide. These existing strategies have limitations, including frequent relapses and toxicity, which highlights the need to explore alternative therapeutic approaches. Glycosides, which are secondary metabolites found in plants, show promise as potential solutions. These substances have a wide range of therapeutic applications, high bioavailability, and low toxicity. They can be used to treat various diseases, both communicable and non-communicable, making them an intriguing class of drugs. However, further research is necessary to uncover their potential value in treating cancer, particularly leukemia. This study aims to investigate the mechanisms of action, effectiveness, and utilization of different glycosides in the treatment of leukemia, while considering the current limitations of existing therapies.
... A kind of acute non-lymphocytic leukaemia otherwise called acute myeloid leukaemia (AMl) is common in adults in which abnormal myeloblasts are produced by the bone marrow. Since the early signs of AMl, a heterogeneous disease of blood stem cells, are sometimes identical to those of other serious illnesses, diagnosis can be challenging [110]. Blood and bone marrow smears are used to identify leukemic myeloblasts which are used in the diagnosis [111]. ...
Cancer has a devastating impact globally regardless of gender, age, and community, which continues its severity to the population due to the lack of efficient strategy for the cancer diagnosis and treatment. According to the World Health Organisation report, one out of six people dies due to this deadly cancer and we need effective strategies to regulate it. In this context, trace element has a very hidden and unexplored role and require more attention from investigators. The variation in concentration of trace elements was observed during comparative studies on a cancer patient and a healthy person making them an effective target for cancer regulation. The percentage of trace elements present in the human body depends on environmental exposure, food habits, and habitats and could be instrumental in the early diagnosis of cancer. In this review, we have conducted inclusive analytics on trace elements associated with the various types of cancers and explored the several methods involved in their analysis. Further, intricacies in the correlation of trace elements with prominent cancers like prostate cancer, breast cancer, and leukaemia are represented in this review. This comprehensive information on trace elements proposes their role during cancer and as biomarkers in cancer diagnosis.
... 9,10 AML is an aggressive malignancy same as ALL and it is characterized by accumulation of immature myeloid progenitors in the bone marrow. 11 It is the most common childhood malignancy in Bangladesh also. 12 The relative survival rate is also very high in case of childhood acute leukaemia. ...
Background: Leukemia is one of the most common tumors in children. Childhood acute leukaemia (AL) is a heterogenous disease. Immunophenotyping is an essential part of the modern diagnostic workup/for typing and subtyping and prognostic stratification of AL and thus for an appropriate treatment of these complex and heterogeneous diseases. Objectives: Objective of this study was to find immunophenotypic charectarization of childhood acute leukemia in children of Bangladesh. There is very limited study done on this subject in our country. Methods: This is a retrospective observational study done in children with acute leukemia under 15 years of age, treated in two tertiary care centers for Paediatric Oncology [Combined Military Hospital Dhaka and Ahsania Mission Cancer Hospital, Mirpur, Dhaka]. Data were collected from hospital registry from 2014 to 2020 and then analyzed. Results: Total study population were 82; among them male 55%, female 45% and M:F 1:0.82. Most common age group was <5 years age with 55% patients. Disease distribution showed 77% patients had ALL and 23% AML. Among ALL, subtype distribution showed B-cell type 90.5% T-cell type 9.5%. A good number of patients did Immuno-phenotyping analaysis before starting chemotherapy, 68 out of 82 acute leukemia patients (83%). In case of B-ALL highest expression of antigen was CD19 (90%) followed by CD10 (76%), HLADR (76%), CD22 (74%), CD79a (68%), TdT (56%) and CD34 (48%). co-expression of CD10/19was seen in 38% cases. Even in 13% cases, expression of myeloid marker CD13 (14%) and T cell marker CD5 (2%) were seen. In case of T-ALL there was 100% expression of CD3. Expression of other antigen CD4, CD5, CD7, CD45, TdT was 33.33% in each. Expression of CD10, CD1a, CD2 and TCRAb also found 33.33% in each. In case of AML highest expression was MPO (93.24%) followed by CD33 (86.58%), CD13 (79.92%), CD117 (73.26%), CD45 (66%), HLADR (46.62%) and CD64 (46.62%). There was 6.66% aberrant expression of B cell marker CD19 and and T-cell marker CD3 (6.66%), CD5 (6.66%) and CD7 (6.66%). Conclusion: In this study we found in case of B-ALL there was maximum expression was CD19 (90%), 2% aberrant expression of T-ALL marker CD5 and 14% aberrant expression of myeloid marker CD13 were present. In case of T-ALL maximum expression was CD3 (100%). In case of AML there was maximum expression of MPO (93%) and CD33 (87%) along with aberrant expression of B cell marker CD19 (6.66%) and 6.66% of each T cell marker CD3, CD5 and CD7 were present. DS (Child) H J 2022; 38(2): 96-102
... It is distinguished by the fast propagation of aberrant cells found in the bone marrow, which interferes with the normal blood cells' development, the most commonly diagnosed leukemia in adults (25%) and comprises 15-20% in children. 1,2,3 Leukemic blasts and immune system cells can both produce cytokines in AML patients, although it is unclear what function they play in the etiology of the disease and their role in the pathophysiology of acute leukemia is not entirely understood. Therefore, leukemia is characterized by aberrant cytokine signaling that may contribute to The aberrant cytokine signaling is a leukemia feature that may contribute to proliferation, blast survival, therapy resistance, and patient prognosis, leukemic blasts from many AML patients, unlike normal hematopoietic cells, release cytokines such as IL-1, GM-CSF, G-CSF, IL-6, IL-8, TNF-α, and SCF 2 . ...
Acute myelogenous leukemia (AML) is a varied group of biological and clinical diseases. It is distinguished by the fast proliferation of aberrant cells in the bone marrow, which interferes with normal blood cell formation. Several studies demonstrated that cytokines released by leukemic cells in an autocrine or paracrine manner influence the proliferation of AML cells. Our study aimed to assess serum levels of TLR-9, TNF-α and, IL-6 in patients of AML. The study was done via the ELISA Technique. The results show a highly significant difference in all parameters in Patients and control. The correlation between immunological parameters using the Pearson correlation coefficient for patients showed that there is a weak correlation between TLR-9 and TNF- α, IL-6 with P-values of 0.47 and 0.23 respectively. This may indicate the complex environment of inflammation. However, there was a strong correlation between TNF- α and IL-6 with a P-value (0.001). This indicates that the secretion of these cytokines was high in patients. All immunological parameters of patients were evaluated using the receiver operating characteristic (ROC) curve to demonstrate that any one of them is a useful tool for identifying and tracking inflammation. The ROC curve's findings revealed that all parameters have good sensitivity and specificity for detecting inflammation and disease activity in AML patients. According to the current study, AML was related to higher levels of TLR-9, TNF-α, and, IL-6 may be affected the prognosis of the disease, increase the risk of the disease progression, and may be used as a biomarker to target AML cells.
... International Journal of Molecular and Cellular Medicine. 2023; 12(1): [18][19][20][21][22][23][24][25][26][27][28][29] Introduction Acute myeloid leukemia is an invasive form of hematologic malignancies, characterized by an increase in the number of myeloid cells in the bone marrow and differentiation arrest of myeloid progenitor cells (1,2). Based on the French-American-British (FAB) system, there are eight types of AML (M0-M7), which are different in morphological characteristics and the degree of leukemic-cell differentiation (3). ...
Acute myeloid leukemia (AML) is an invasive form of hematologic malignancies which results in the overproduction of myeloid cells in the bone marrow. Aberrant expression of piwi-interacting RNAs (piRNAs) which belong to small non-coding RNAs, play important roles in different cancer cells' progress. hsa- piR- 32877 is up-regulated in AML. Down regulation of hsa-piR-32877 by antisense LNA GapmeRs could be potential for suppression of myeloid cell proliferation and induce myeloid cell apoptosis. We have blocked the expression of hsa-piR-32877 by antisense LNA GapmeRs in human bone marrow blast cells, and the M-07e cell line. Samples were transfected with antisense LNA GapmeRs at 24, 48, and 72 hours. The Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to investigate the expression of hsa-piR-32877, CASP3, and CASP9. Both CASP3 and CASP9 play important roles in apoptosis. Cell proliferation was studied via CFSE (carboxyfluorescein diacetate succinimidyl ester) assay. Results showed that hsa-piR-32877 was down-regulated by antisense LNA GapmeRs in the patient and cell line samples. Also, after transfection, cell proliferation and apoptosis decreased and increased, respectively. Our data suggested that hsa-piR-32877 suppression may act as a novel therapeutic method for the inhibition of human leukemic cells proliferation in AML.
... For RNA isolation from the whole blood, PBMC pellet was isolated first. The RNA extraction procedure was adopted from previous published studies (Lowenberg et al., 1999;Slovaket al., 2000). ...
... AML arises from molecular alterations at the HSPC level. Alike in healthy hematopoiesis, LSCs are the origin of clonal growth and therefore considered responsible for maintenance of the leukemic population (44,45). Given the central role of LSCs in development and pathogenesis of leukemic disease (1,2), therapeutic elimination of this population is central to prevent relapses. ...
Therapy-resistant leukemia stem and progenitor cells (LSC) are a main cause of acute myeloid leukemia (AML) relapse. LSC-targeting therapies may thus improve outcome of patients with AML. Here we demonstrate that LSCs present HLA-restricted antigens that induce T-cell responses allowing for immune surveillance of AML. Using a mass spectrometry–based immunopeptidomics approach, we characterized the antigenic landscape of patient LSCs and identified AML- and AML/LSC-associated HLA-presented antigens absent from normal tissues comprising nonmutated peptides, cryptic neoepitopes, and neoepitopes of common AML driver mutations of NPM1 and IDH2. Functional relevance of shared AML/LSC antigens is illustrated by presence of their cognizant memory T cells in patients. Antigen-specific T-cell recognition and HLA class II immunopeptidome diversity correlated with clinical outcome. Together, these antigens shared among AML and LSCs represent prime targets for T cell–based therapies with potential of eliminating residual LSCs in patients with AML.
Significance
The elimination of therapy-resistant leukemia stem and progenitor cells (LSC) remains a major challenge in the treatment of AML. This study identifies and functionally validates LSC-associated HLA class I and HLA class II–presented antigens, paving the way to the development of LSC-directed T cell–based immunotherapeutic approaches for patients with AML.
See related commentary by Ritz, p. 437 .
... The approval of new drugs by the US Food and Drug Administration (FDA) for the treatment of acute myeloid leukemia (AML) has led to significant progress in the chemotherapy regimens used for initial treatment. This has resulted in a 70% to 80% complete remission (CR) rate among adult AML patients [1,2]. However, approximately 30% of patients fail to achieve CR after two cycles of chemotherapy, and around 50% of patients experience relapse within 3 years of achieving CR through chemotherapy alone, leading to R-R AML [3][4][5][6]. ...
Patients with relapsed and refractory acute myeloid leukemia (R-R AML), especially those in non-remission (NR) have a poor prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to optimize the entire allo-HSCT process for R-R AML patients and identify potential factors affecting clinical outcomes after HSCT, we retrospectively analyzed 44 adult patients with R-R AML who underwent salvage allo-HSCT while in NR or with concomitant extramedullary leukemia at the Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from 2013 to 2022. The 1-year and 2-year overall survival (OS) of the 44 patients were 55.3% (95% confidence interval [CI], 41.1%-74.3%) and 44.4% (95%CI, 30.2%-65.4%), respectively. The 1-year and 2-year cumulative incidence of relapse (CIR) were 39.4% (95%CI, 38.0%-40.7%) and 53.0% (95%CI, 51.0%-55.1%), respectively, and the 1-year and 2-year leukemia-free survival (LFS) were 37.8% (95%CI, 24.8%-57.7%) and 20.3% (95%CI, 9.1%-45.3%), respectively. The 100-day, 1-year and 2-year treatment-related mortality (TRM) was 13.8% (95%CI, 13.3%-14.4%), 22.8% (95%CI, 21.9%-23.7%) and 26.7% (95%CI, 25.5%-27.8%), respectively. Multivariate analysis revealed that patients who developed chronic graft-versus-host disease (cGVHD) after transplantation had lower relapse rate. Our analysis also indicated that patients with blast counts in bone marrow (BM) <20% and those with ≥20% had comparable clinical outcomes after allo-HSCT. In conclusion, our study demonstrated that R-R AML patients in NR or with concomitant extramedullary leukemia can benefit from allo-HSCT, regardless of leukemia burden at the time of transplantation. Patients who experience cGVHD after allo-HSCT may have lower relapse rate due to enhanced graft-versus-leukemia (GVL) effects, but cGVHD should be controlled at mild to moderate level to avoid life-threatening complications.
... 7 Although new treatments have been introduced and there have been notable advancements in the long-term outcomes of patients in recent decades, AML still has a poor prognosis overall. 2,8 While young patients respond to therapy and achieve complete remission after induction chemotherapy, 2,8,9 older patients exhibit distinct clinical courses, with the majority experiencing a relapse. 2,10 This discrepancy can be attributed to the significant heterogeneity of AML, which encompasses cytogenetic and molecular abnormalities along with individual factors such as physical conditions and comorbidities. ...
The advancement of diverse technologies has led to a substantial increase in valuable biomedical data, particularly in the field of acute myeloid leukemia (AML). Effective utilization of this wealth of data is crucial for attaining a comprehensive and in‐depth understanding of AML, thereby facilitating optimal diagnosis, treatment, and prognosis. Among the various approaches to data acquisition, single‐cell sequencing has emerged as an impressive tool. The developments of single‐cell sequencing methods have empowered researchers to analyze the genome, transcriptome, proteome, and epigenome data at the single‐cell level. It also offers a means to uncover fine information, providing unique prognostic insights and aiding in the identification of therapeutic targets. Furthermore, it enhances our understanding of AML heterogeneity, clonal evolution, and resistance mechanisms, ultimately leading to the development of better treatment strategies. In this review, we present an overview of AML as well as single‐cell sequencing technologies, then explore their potential contributions to AML research in different aspects, and provide some information about resources and data processing.
... [1][2][3] Consolidation regimens with intermediate-dose cytarabine (IDAC) and high-dose cytarabine of 3 g/m 2 /dose (HDAC) chemotherapy can significantly prolong the remission period of the patients and improve their prognosis. 1,[4][5][6] Repetitive cycles of HDAC twice a day, on days 1, 3, and 5 over a total 5 day period (HDAC-135) have become widely accepted as standard protocol for AML consolidation therapy [7][8][9] after the landmark trial by the Cancer and Leukemia Group B (CALGB). 10 However, in recent years, multiple new studies have emerged which challenge the benefits of HDAC-135. 11 The German-Austrian AML Study Group found faster hematologic recovery and lower infection rates with HDAC on days 1-3 consecutively (HDAC-123). ...
Introduction
The last decade has seen advances in delivering outpatient consolidation therapy for acute myeloid leukemia (AML). The standard of care involves high‐dose cytarabine or intermediate‐dose cytarabine, given twice daily for three alternating days. At the London Regional Cancer Program, we have transitioned the administration of outpatient cytarabine to a once‐daily regimen over six consecutive days. The outcomes of a longer duration interval of high‐dose cytarabine and intermediate‐dose cytarabine is currently unknown. This study aims to assess the feasibility of administering a continuous 6‐day protocol of high‐dose (HDAC‐16) and intermediate‐dose cytarabine (IDAC‐16) consolidation therapy in the outpatient setting.
Methods
This is a retrospective chart review to analyze AML patients treated with outpatient high‐dose or intermediate‐dose cytarabine consolidation therapy at the London Regional Cancer Program from January 1, 2019, through November 1, 2022. The primary objective was to determine the outcomes of the 6‐day outpatient administration of once daily high‐dose cytarabine or intermediate‐dose cytarabine.
Results
Forty‐five patients received 89 cycles of cytarabine as outpatients; males were 55.6% of the total population, with a median age of ~57 years. Our overall 2‐year survival of HDAC‐16 (57.1%) and IDAC‐16 (83.3%) is consistent with the reported literature. There was no difference in delays, relapse rates, and nonrelapse mortality between both HDAC and IDAC groups. The 2‐year relapse free survival was 57.1% for HDAC‐16 and 66.7% for IDAC‐16.
Conclusion
Outpatient administration of intermediate‐dose cytarabine once daily over six consecutive days results in similar overall survival and relapse rates as compared to high dose cytarabine consolidation chemotherapy. Moving to a once daily administration schedule can alleviate logistical and/or accessibility hurdles for outpatient oncology clinics. Prospective randomized trials are needed in this setting to validate our results.
... Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic system characterized by uncontrolled cell proliferation, impaired cell differentiation, and in ltration of bone marrow, peripheral blood, or other tissues [35]. A crucial protein involved in various cellular processes, such as cell proliferation, apoptosis, and transcription, is Akt, also known as protein kinase B (PKB) or Rac. ...
To investigate the antiproliferative activity associated with the piperazine framework, a series of benzhydryl piperazine derivatives 8–18 were synthesized and characterized both spectroscopically and structurally. The antiproliferative activity of these compounds against eight human tumor cell lines was assessed. Among the tested compounds, compound 11 exhibited the highest potency, effectively inhibiting the proliferation of three selected human cancer cell lines, HL-60, Z138, and DND-41 with IC 50 values of 16.80, 18.50 and 19.20 µM, respectively. Compound 10 displayed IC 50 values of 19.90, 18.00 and 18.50 µM against the cell lines HL-60, Z138 and DND-41, whereas compound 13 showed IC 50 value of 19.90 µM against cell line DND-41. However, all compounds exhibited IC 50 values ranging from 22.95 and 58.45 µM against other tested cancer cell lines. These finding suggest that derivative 11 would be a promising potential lead compound for the development of novel antiproliferative agents. Further compounds 8–18 were evaluated for their antioxidant activity. Additionally, predictive docking studies were performed on the three-dimensional structures of acute myeloid leukemia (CDK2/cyclin A2, PDB: 7B7S, and protein kinase Akt1 PKB alpha, PDB: 4GV1).
... Furthermore, older patients with poor performance score of ECOG ≥3 had a mortality rate of 82% compared to 29% in younger patients with the same performance score [1]. The rates of CR with 7 + 3 induction vary widely in elderly adults (35-60%) and this range drops significantly over time, with no more than 10-20% of patients in their first CR living beyond 3 years from initial diagnosis [10,11,17]. ...
Background:
Acute myeloid leukemia (AML) is a disease of the hematopoietic system that remains a therapeutic challenge despite advances in our understanding of the underlying cancer biology in the past decade. It is also an affliction of the elderly that predominantly affects patients above 60 years of age. Standard therapy involves intensive chemotherapy that is often difficult to tolerate in older populations. Fortunately, recent developments in molecular targeting have shown promising results in treating leukemia, paving the way for novel treatment strategies that are easier to tolerate.
Summary:
Venetoclax, a BCL-2 inhibitor, when combined with a hypomethylating agent, has proven to be a highly effective and well-tolerated drug, and established itself as a new standard for treating AML in patients who are unfit for standard intensive therapy. Other targeted therapies include clinically proven and FDA approved agents, such as IDH1/2 inhibitors, FLT3 inhibitors, and Gemtuzumab, as well as newer and more experimental drugs such as magrolimab, PI-kinase inhibitors, and T-cell engaging therapy. Some of the novel agents such as magrolimab and menin inhibitors are particularly promising, providing therapeutic options to a wider population of patients than ever before. Determining who will benefit from intense or novel low intense therapy remains a challenge and it requires careful assessment of individual patient's fitness and disease characteristics.
Key messages:
This article reviews past and current treatment strategies that harness various mechanisms of leukemia-targeting agents and introduces novel therapies on the horizon aimed at exploring therapeutic options for elderly and unfit patient population. It also provides a strategy to select the best available therapy for elderly patients with both newly diagnosed and relapsed/refractory AML.
... Internal quality checks were performed on all levels (low, normal, and high), calibration was performed once a year, and manufacturer-based standard operating procedures were followed. The blast count in the peripheral smear cut off 20% was considered in all of the acute leukemia cases 6 WBC differential (WDF) (SSCSFL) side scatter (SSC) and side fluorescence (SFL), WDF (SSCFSC) SSC and forward scatter (FSC), WDF (FSCSFL) forward scatter (FSC) and SFL, and white cell nucleated (WNR) (SFLFSC), WNR (SSCFSC), and WNR (SFLSSC) scattergrams were analyzed. All samples were evaluated using peripheral blood smears and bone marrow smears stained with Leishman stain. ...
Background: Scatter grams-graphic depictions of the cell populations in a blood sample are produced by automated analyzers. These scatter grams can be employed to screen for various hematological conditions, including anemia, leukemia, and other blood disorders by examining the scatter gram’s cell population distribution and patterning. Aims and Objectives: In this study, we wish to study the scatter grams generated by the Sysmex XN-series analyzer for confirmed cases of hematological malignancies. Materials and Methods: In this study, 58 cases of hematologic malignancies diagnosed based on peripheral smear findings and bone marrow morphology data were extracted. We retrieved the complete blood count and scatter gram patterns analyzed by Sysmex XN-1000 analyzer for these cases along with peripheral smear findings. Scatter gram patterns in white blood cell differential and white cell nucleated were analyzed correlating with peripheral smears. Results: Among 58 cases, 20 cases were acute myeloid leukemia (6 were acute promyelocytic leukemia), 32 cases were chronic myeloid leukemia, and 5 cases were chronic lymphocytic leukemia. Unique scatter gram patterns were seen with different leukemias. Conclusion: Pattern analysis of scatter grams has the potential to improve the efficiency and accuracy of leukemia diagnosis and also help to prioritize the evaluation of cases that require further testing, such as molecular and cytogenetic evaluations, especially in limited resources or high sample volumes conditions.
... Acute myeloid leukemia (AML) is a malignancy of bone marrow (BM) characterized by differentiation arrest and the uncontrolled proliferation of myeloid progenitors, known as blasts [1]. AML is the most common form of leukemia in adults and the second most common in children, with an overall 5-year survival rate of 30.5% [2]. ...
Simple Summary
Acute myeloid leukemia (AML) is a difficult-to-treat cancer, and chemotherapy can cause severe side effects. Patients may need stem cell transplantation, but this is challenging and not always successful. Even with intensive treatment, some patients may relapse or develop a refractory disease. Genetically modifying some white blood cells, called lymphocytes, with specific molecules called chimeric antigen receptors (CARs) can generate new therapies that can target AML. In this study, we gather all current data from the literature regarding the clinical testing of CAR-based therapies against AML. Moreover, we analyze the limitations of the most established therapy, CAR-T cells (T-lymphocytes with CARs). Additionally, we provide some insights into the potential benefits of using alternative lymphocytes, such as the CAR-NK cells (natural killer cells with CARs).
Abstract
Acute myeloid leukemia (AML) is a devastating disease. Intensive chemotherapy is the mainstay of treatment but results in debilitating toxicities. Moreover, many treated patients will eventually require hematopoietic stem cell transplantation (HSCT) for disease control, which is the only potentially curative but challenging option. Ultimately, a subset of patients will relapse or have refractory disease, posing a huge challenge to further therapeutic decisions. Targeted immunotherapies hold promise for relapsed/refractory (r/r) malignancies by directing the immune system against cancer. Chimeric antigen receptors (CARs) are important components of targeted immunotherapy. Indeed, CAR-T cells have achieved unprecedented success against r/r CD19+ malignancies. However, CAR-T cells have only achieved modest outcomes in clinical studies on r/r AML. Natural killer (NK) cells have innate anti-AML functionality and can be engineered with CARs to improve their antitumor response. CAR-NKs are associated with lower toxicities than CAR-T cells; however, their clinical efficacy against AML has not been extensively investigated. In this review, we cite the results from clinical studies of CAR-T cells in AML and describe their limitations and safety concerns. Moreover, we depict the clinical and preclinical landscape of CAR used in alternative immune cell platforms with a specific focus on CAR-NKs, providing insight into the future optimization of AML.
... Cyt is an important drug in the treatment of acute myeloid leukemia (AML) (4). High-dose cytarabine (2000 to 3000 mg per square meter of body surface area) is toxic but provides higher relapse-free survival rates than the conventional dose of 100 to 400 mg per square meter (5,6). Cyt has been one of the cornerstone drugs in the treatment of acute myeloid leukemia (AML) for over three decades. ...
Cytarabine (Cyt) (also known as cytosine arabinoside (ara-C)) used in the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL). CYT applied in high doses for treatment can cause renal failure. Monitoring excreted urine drug levels can help kidney failure. For this reason, a method was developed and validated by HPLC-MSMS for urine CYT analysis, which is not included in the literature. In this study, a liquid chromatography (HPLC) with triple quadrupole Mass Spectrometric (MS/MS) method developed for the determination of Cyt from urine for toxicokinetic evaluation. Positive MRM mode selected for the quantification of Cyt. The product and major fragment ion for Cyt 244.0 > 112.0 m/z, for IS 198.0 > 152.0 m/z. The optimal MS parameters for Cyt and IS are as follows Fragmentor 80 V, 70 V, Collision energy, 6, 9 respectively. A novel simple, high-throughput and highly sensitive HPLC-MS/MS method was successfully developed and validated for the determination of Cyt from urine. The developed method has a simple one-step extraction method and a short run time (2.0 minutes) for analysis. The proposed method could be practical and reliable for excretion and toxicokinetic studies and as well as the Therapeutic Drug Monitoring study in humans without an invasive route for Cyt.
... The annual incidence is around 2.4 cases per 100,000 individuals and it increases progressively with age, to a peak of 12.6 per 100,000 in adults of 65 years of age or older. 1 A proportion of AML cases does not present as a de novo disease but represents the clinical evolution of clonal HSC disorders such as myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN). In recent years, there have been major advances in our understanding of AML, including new knowledge about the molecular pathogenesis, leading to an update of the disease classification, 2,3 technological progress in genomic diagnostics and assessment of minimal residual disease, 4,5 and the successful development of new therapeutic agents. ...
Until a few years ago, the onset of acute myeloid leukemia (AML) was entirely ascribed to genetic lesions in hematopoietic stem cells. These mutations generate leukemic stem cells, which are known to be the main ones responsible for chemoresistance and relapse. However, in the last years, increasing evidence demonstrated that dynamic interplay between leukemic cells and bone marrow (BM) niche is of paramount relevance in the pathogenesis of myeloid malignancies, including AML. Specifically, BM stromal niche components, such as mesenchymal stromal cells (MSCs) and their osteoblastic cell derivatives, play a key role not only in supporting normal hematopoiesis but also in the manifestation and progression of myeloid malignancies. Here, we reviewed recent clinical and experimental findings about how genetic and functional alterations in MSCs and osteolineage progeny can contribute to leukemogenesis and how leukemic cells in turn generate a corrupted niche able to support myeloid neoplasms. Moreover, we discussed how the newest single-cell technologies may help dissect the interactions between BM stromal cells and malignant hematopoiesis. The deep comprehension of the tangled relationship between stroma and AML blasts and their modulation during disease progression may have a valuable impact on the development of new microenvironment-directed therapeutic strategies, potentially useful for a wide cohort of patients.
... The RUNX1::RUNX1T1 (AML1/ETO) fusion results from a translocation between chromosomes 8 and 21 {t (8; 21) (q 22; q22)} [1][2][3]. In the context of intensive chemotherapy based on cytarabine at a high dose of 3000 mg/m 2 , CBF leukaemia has a more favourable outcome [4][5][6]. Although CBF-AML is considered a favourable risk AML, long-term follow-up reports from larger groups showed a median overall survival (OS) of ~ 5 years or less, and approximately 40-50% of CBF leukaemia patients relapse after standard chemotherapy [4,[7][8][9]. ...
Acute myeloid leukaemia (AML) with t (8;21) or inv (16), called core binding factor (CBF) AML, has a favourable prognosis. However, some CBF-AML patients have persistent measurable residual disease (MRD) and are more likely to relapse after standard chemotherapy treatment. The CAG regimen, composed of cytarabine, aclarubicin and granulocyte colony-stimulating factor, has been proven to be effective and safe in treating refractory AML patients. We performed a retrospective study to evaluate the efficacy of the CAG regimen to eliminate MRD detected by RUNX1::RUNX1T1 and CBFβ::MYH11 transcript levels by quantitative polymerase chain reaction (Q-PCR) among 23 patients. Molecular response was defined as the ratio of fusion transcript after treatment to that before treatment less than or equal to 0.5. The molecular response rate and median decrease ratio of fusion transcripts at the molecular level of the CAG regimen were 52% and 0.53, respectively. The median fusion transcripts before CAG treatment was 0.25% whereas after CAG was 0.11%. Among the 15 patients who had a poor molecular response to the high/intermediate-dose cytarabine regimen, the median decrease ratios of transcripts at the molecular level of high/intermediate-dose cytarabine and CAG were 1.55 and 0.53 (P = 0.028), respectively, and 6 of 15 patients achieved a molecular response to CAG (40%). The median disease-free survival was 18 months, and the overall survival rate at 3 years among all patients was 72.7% ± 10.7%. The common grades 3–4 adverse events were nausea (100%), thrombocytopenia (39%) and neutropenia (37.5%). The CAG regimen may have activity in CBF-AML patients and could provide a new option for patients who have a poor molecular response to high/intermediate-dose cytarabine.
... Acute myeloid leukemia (AML), which is highly heterogeneous in adults, represents the most common hematologic malignancy worldwide (1)(2)(3). The American Cancer Society has reported a diagnoses rate of more than 20000 new cases of AML in 2021 in the United States alone, while the 5-year overall survival rate is lower than 30% (4). ...
Acute myeloid leukemia (AML) is a highly aggressive cancer with great heterogeneity and variability in prognosis. Though European Leukemia Net (ELN) 2017 risk classification has been widely used, nearly half of patients were stratified to “intermediate” risk and requires more accurate classification via excavating biological features. As new evidence showed that CD8+ T cell can kill cancer cells through ferroptosis pathway. We firstly use CIBERSORT algorithm to divide AMLs into CD8+ high and CD8+ low T cell groups, then 2789 differentially expressed genes (DEGs) between groups were identified, of which 46 ferroptosis-related genes associated with CD8+ T cell were sorted out. GO, KEGG analysis and PPI network were conducted based on these 46 DEGs. By jointly using LASSO algorithm and Cox univariate regression, we generated a 6-gene prognostic signature comprising VEGFA, KLHL24, ATG3, EIF2AK4, IDH1 and HSPB1. Low-risk group shows a longer overall survival. We then validated the prognostic value of this 6-gene signature using two independent external datasets and patient sample collection dataset. We also proved that incorporation of the 6-gene signature obviously enhanced the accuracy of ELN risk classification. Finally, gene mutation analysis, drug sensitive prediction, GSEA and GSVA analysis were conducted between high-risk and low-risk AML patients. Collectively, our findings suggested that the prognostic signature based on CD8+ T cell-related ferroptosis genes can optimize the risk stratification and prognostic prediction of AML patients.
Despite more than 200 approved anticancer agents, cancer remains a leading cause of death worldwide due to disease complexity, tumour heterogeneity, drug toxicity, and the emergence of drug resistance. Accordingly, the development of chemotherapeutic agents with higher efficacy, a better safety profile, and the capability of bypassing drug resistance would be a cornerstone in cancer therapy. Natural products have played a pivotal role in the field of drug discovery, especially for the pharmacotherapy of cancer, infectious, and chronic diseases. Owing to their distinctive structures and multiple mechanistic activities, natural products and their derivatives have been utilized for decades in cancer treatment protocols. In this review, we delve into the potential of natural products as anticancer agents by targeting cancer’s hallmarks, including sustained proliferative signalling, evading growth suppression, resisting apoptosis and cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. We highlight the molecular mechanisms of some natural products, in vivo studies, and promising clinical trials. This review emphasizes the significance of natural products in fighting cancer and the need for further studies to uncover their fully therapeutic potential.
Hydroxyurea, a myelosuppressive agent, is the only effective drug proven to reduce the frequency of painful episodes Hydroxyurea (Hydrea) is used alone or with other medications or radiation therapy to treat a certain type of chronic myelogenous leukemia (CML; a type of cancer of the white blood cells) and certain types of head and neck cancer (including cancer of the mouth, cheek, tongue, throat, tonsils, and sinuses).
It works by making the red blood cells more flexible. It can also treat head and neck cancer and pain from sickle cell anemia. It usually decreases the rate of painful episodes by 50 %. It was first tested in sickle cell disease in 1984. It also decreases the rate of ACS episodes and blood transfusions by ~50 % in adults. It was developed as an anticancer drug and has been used to treat myeloproliferative syndromes-leukemia, melanoma, and ovarian cancer. It was approved for use by FDA in adults. Side effects includes neutropenia, bone marrow suppression, elevation of hepatic enzymes, anorexia, nausea, vomiting and infertility.
Hydroxyurea is used to prevent painful episodes and reduce the need for blood transfusions in patients with sickle cell anemia
Key words: Hydroxyurea, Leukemia, anemia
Most of the genome is transcribed into RNA but only 2% of the sequence codes for proteins. Non-coding RNA transcripts include a very large number of long noncoding RNAs (lncRNAs). A growing number of identified lncRNAs operate in cellular stress responses, for example in response to hypoxia, genotoxic stress, and oxidative stress. Additionally, lncRNA plays important roles in epigenetic mechanisms operating at chromatin and in maintaining chromatin architecture. Here, we address three lncRNA topics that have had significant recent advances. The first is an emerging role for many lncRNAs in cellular stress responses. The second is the development of high throughput screening assays to develop causal relationships between lncRNAs across the genome with cellular functions. Finally, we turn to recent advances in understanding the role of lncRNAs in regulating chromatin architecture and epigenetics, advances that build on some of the earliest work linking RNA to chromatin architecture.
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy primarily driven by an immature population of AML cells termed leukemia stem cells (LSCs) that are implicated in AML development, chemoresistance, and relapse. An emerging area of research in AML focuses on identifying and targeting the aberrant metabolism in LSCs. Dysregulated metabolism is involved in sustaining functional properties of LSCs, impeding myeloid differentiation, and evading programmed cell death, both in the process of leukemogenesis and in response to chemotherapy. This review discusses recent discoveries regarding the aberrant metabolic processes of AML LSCs that have begun to change the therapeutic landscape of AML.
Background: Acute myeloid leukemia (AML) is a malignant disorder of the hematopoietic stem cells characterized by abnormal proliferation of myeloid blast cells in the bone marrow and blood, preventing them from further differentiating into the specialized cells of the bone marrow and thus causing pancytopenia. Consequently, AML can affect various tissues and organs (liver, skin, central nervous system), including the eye and orbit. Ophthalmic manifestations of leukemia are more frequent with acute than chronic leukemia. It can affect all intraocular structures. Methods: We present a 17 year old male student with AML, who developed severe painless progressive reduction of vision. Visual acuity (VA) was found to be Hand Movement (HM) in both eyes. Patient's ocular B-scan showed every other ocular structure to be normal except the retina and vitreous. They showed some areas of tumor deposit and some atrophic areas. Patient was counseled on reason for reduction in vision and referred to the optometry clinic for expert management. Patient was referred to Low Vision unit for low vision assessment as there was no improvement after refraction. Results: There was a great improvement from HM to 6/5 after assessment, training and prescription of low vision aids. Conclusions: Hope was restored when low vision aids were prescribed. Everybody deserves functional vision notwithstanding life expectancy as long there's life.
Herein, a novel series of 1,5‐disubstituted‐1,2,3‐triazolines containing 1‐(4‐chlorobenzhydryl) piperazine moiety (8–18) were synthesised and evaluated for their anticancer activity across eight human tumor cell lines. Remarkably, compound 11 substituted with 3‐acetylphenyl group was the most potent anticancer agent against three selected human cancer cell lines (HL‐60, Z138, and DND‐41) with IC50 values of 16.80, 18.50, and 19.20 μM, respectively. In contrast, analogue 10 demonstrated activity against HL‐60, Z138, and DND‐41 cell lines, with IC50 values of 19.90, 18.00, and 18.50 μM, respectively. Moreover, derivative 13 substituted with 4‐bromophenyl moiety displayed activity with IC50=19.90 μM against the DND‐41 cell line. However, all analogues showed IC50 values ranging from 22.95 to 58.45 μM when tested against other investigated cancer cell lines. These findings suggest that derivative 11 holds promise as a potential candidate for synthesizing novel anticancer agents. Furthermore, compounds 8–18 were screened for their antioxidant activity. Molecular docking studies of compound 11 on crystal structures of two proteins, CDK2/cyclin A2 (PDB: 7B7S) and kinase Akt1 PKB alpha (PDB: 4GV1) have been studied.
Melatonin (N-acetyl-5-methoxytryptamine, MEL), secreted by the pineal gland, plays an important role in the regulation of the different functions in human. However, there are the facts that MEL has an antitumor effect in various types of cancer. We have studied the combined effect of MEL and targeted drugs such as cytarabine (CYT) and navitoclax (ABT-737) on the development of acute myeloid leukemia in the MV4-11 cell model. The combined action of MEL with CYT or ABT-737 contributed to a decrease in the proliferative activity of leukemia cells, a drop in the membrane potential of mitochondria, and an increase in the production of reactive oxygen species and cytosolic Ca2+. We have shown that MEL, together with CYT or ABT-737, increases expression of homologous C/EBP protein and autophagy marker LC3A/B and decreases protein disulfide isomerase and immunoglobulin-binding protein levels, and consequently modulate endoplasmic stress. reticulum and initiate autophagy. The obtained data support the earlier suggestion that MEL may have potential benefits in cancer treatment and may be considered as an additive to drugs used in therapy.
Every 3 minutes, someone is diagnosed with a blood cancer or disease, which often requires a blood stem cell transplant. The majority of these patients do not have a match in their family. Be The Match® is a blood stem cell donor registry that connects patients to matching donors. People ages 18-40 who meet the health guidelines are able to join the registry. It is more likely that a patient will match with a donor of their ethnic background, making a diverse college campus an excellent place to hold a donor registration event.
A leucemia corresponde ao conjunto de neoplasias malignas resultantes de uma falha na hematopoese, ou seja, quando, ocorrendo uma proliferação e acúmulo excessivo das células precursoras, há um comprometimento no desenvolvimento e no funcionamento das células sanguíneas. As leucemias são consideradas diferentes dos demais tipos de câncer, devido seu desenvolvimento, já que para sua disseminação, não são necessários mecanismos de angiogênese, ruptura estrutural, e de produção de metástase, que são frequentes nos demais. Face o exposto, fica evidenciado a gravidade e importância da patologia, sendo importante mapear epidemiologicamente, visto que pode acarretar um maior controle para sobrecargas dos serviços de saúde, e proporcionar de forma mais enfática o maior controle de novos casos.
Current treatment selection for acute myeloid leukemia (AML) patients depends on risk stratification based on cytogenetic and genomic markers. However, the forecasting accuracy of treatment response remains modest, with most patients receiving intensive chemotherapy. Recently, ex vivo drug screening has gained traction in personalized treatment selection and as a tool for mapping patient groups based on relevant cancer dependencies. Here, we systematically evaluated the use of drug sensitivity profiling for predicting patient survival and clinical response to chemotherapy in a cohort of AML patients. We compared computational methodologies for scoring drug efficacy and characterized tools to counter noise and batch-related confounders pervasive in high-throughput drug testing. We show that ex vivo drug sensitivity profiling is a robust and versatile approach to patient prognostics that comprehensively maps functional signatures of treatment response and disease progression. In conclusion, ex vivo drug profiling can assess risk for individual AML patients and may guide clinical decision-making.
We retrospectively analyzed 155 AML patients with DAT mutations at diagnosis who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at complete remission. Of the 155 AML patients with DAT mutations at diagnosis, 59 (38.1%) patients had persisting DAT mutations pretransplantation. Compared to patients with pretransplant DAT transitions, patients with persisting DAT mutation burden were shown to be older (p = 0.004), and fewer patients had TET2 mutations at diagnosis (p = 0.033). Patients with persistent DAT mutation burden had shorter overall survival (OS) (3-year OS: 59.3% vs. 83.0%, p < 0.001) and disease-free survival (DFS) (3-year DFS: 56.1% vs. 83.0%, p < 0.001) with a higher cumulative incidence of relapse (CIR) (24.6% vs. 17.4%, p = 0.002) than those with DAT transitions. Additionally, multivariate analysis confirmed that persisting DAT mutations were an independent adverse factor for relapse, OS, and DFS. Collectively, persisting DAT mutations prior to allo-HSCT at complete remission for AML correlated with negative outcomes.
Background:
To ascertain the efficacy and safety of cladribine, cytarabine, and filgrastim-based regimen in relapsed or refractory (R/R) AML patients.
Methods:
Clinical studies were searched in PubMed, Cochrane Library, Embase data. We selected available factors including complete remission (CR), overall response rate (ORR), overall survival (OS) to evaluate the efficacy, and early death (ED), and adverse events to evaluate safety.
Results:
15 records with 812 R/R AML patients were finally included and analyzed using the R software. Subgroups analysis was also conducted. The pooled CR rate for CLAG regimen, CLAG-M regimen, and CLAG combined with any other drugs regimen is 56% (95% CI: 46-66), 46% (95% CI: 34-56), 44% (95% CI: 26-64), respectively. The relapsed and refractory groups showed a CR rate of 68% (95% CI: 53-80), and 51% (95% CI: 45-58) with CLAG related regimens. As risk grade decreases, the pooled CR rate increases. Regarding the safety for CLAG-related protocols, systematic review was conducted.
Conclusion:
The CLAG-related regimen is an effective and safe therapy for R/R AML patients, CLAG seems to have more superiority than CLAG combined therapy, though further studies including cladribine combination treatment protocols, are still needed to confirm our results further.
Reticulocalbin‐1 (RCN1) is expressed aberrantly and at a high level in various tumors, including acute myeloid leukemia (AML), yet its impact on AML remains unclear. In this study, we demonstrate that RCN1 knockdown significantly suppresses the viability of bone marrow mononuclear cells (BMMNCs) from AML patients but does not affect the viability of granulocyte colony‐stimulating factor (G‐CSF)‐mobilized peripheral blood stem cells (PBSCs) from healthy donors in vitro. Downregulation of RCN1 also reduces the viability of AML cell lines. Further studies showed that the RCN1 knockdown upregulates type I interferon (IFN‐1) expression and promotes AML cell pyroptosis through caspase‐1 and gasdermin D (GSDMD) signaling. Deletion of the mouse Rcn1 gene inhibits the viability of mouse AML cell lines but not the hematopoiesis of mouse bone marrow. In addition, RCN1 downregulation in human AML cells significantly inhibited tumor growth in the NSG mouse xenograft model. Taken together, our results suggest that RCN1 may be a potential target for AML therapy.
Hematological malignancies(HMs) are highly heterogeneous diseases with globally rising incidence. Despite major improvements in the management of HMs, conventional therapies have limited efficacy, and relapses with high mortality rates are still frequent. Cordycepin, a nucleoside analog extracted from Cordyceps species, represents a wide range of therapeutic effects, including anti-inflammatory, anti-tumor, and anti-metastatic activities. Cordycepin induces apoptosis in different subtypes of HMs by triggering adenosine receptors, death receptors, and several vital signaling pathways such as MAPK, ERK, PI3K, AKT, and GSK-3β/β-catenin. This review article summarizes the impact of utilizing cordycepin on HMs, and highlights its potential as a promising avenue for future cancer research based on evidence from in vitro and in vivo studies, as well as clinical trials.
Venetoclax (VEN) in combination with intensive chemotherapy (IC) is increasingly used to treat patients with high-risk acute myeloid leukemia (AML). We conducted a systematic review to assess the safety and efficacy outcomes of FLAG-IDA in combination with VEN. The primary safety outcome was infection rate; the primary efficacy outcome was response to treatment (composite complete remission (CRc) and overall response rate (ORR). Risk of bias was assessed according to the ROBINS-I tool. Six studies including 221 patients with newly-diagnosed (ND AML (n = 120)) and R/R AML (n = 101) disease, were included in this systematic review. Pooling of results was not conducted due to major differences between studies. The reported rates of neutropenic fever, bacteremia, pneumonia and invasive fungal infections were at 44-55 %, 24-48 %, 12-30 % and 11-36 % of assessed patients, respectively. Time to ANC and platelet recovery ranged between 23 and 29 and 23-31 days, respectively. Early death rate was 8.7 % (14/160) patients: four patients at 30 days, additional ten in 60 days. CRc rates ranged between 53 % and 78 % for R/R AML. CRc for ND was reported by one study only (89 %). ORR were reported in 60-78 % of patients with R/R AML. Only one study reported an ORR for ND patients of 98 %. In our systematic review, FLAG-Ida plus VEN proved to be a potentially tolerable and effective regimen in ND and R/R AML patients. We suggest further evaluation and confirmation for the safety and efficacy of this new protocol in future RCTs.
Presence of leukocytes in huge amount in the bone marrow and blood causes blood cancer or leukemia. In leukemia, number of white blood corpuscles in blood increases rapidly. Chemotherapy treatment is the most useful treatment of leukemia. Although chemotherapy treatment can reduce the cancer cells effectively, it destroys the healthy cells of the body as well. Therefore, it is essential to develop a proper control structure to use the chemotherapy agent effectively to reduce the cancer cells and to keep the normal cells within specified limit. An adaptive boundary layer double integral sliding mode controller is designed in this article for treatment of acute leukemia using chemotherapy. The objective of the designed controller is to control the chemotherapy agent in such a way that the amount of leukemic cell become zero and at the same time, the number of healthy cells should be retained at a desired level. The stability of the designed controller is verified using a Lyapunov function. The consequences of chemotherapy treatment on both natural cells and cancer cell using the designed controller is observed in both monotonic and non‐monotonic therapy function. A comparative analysis is also carried out between the designed controller and some existing controller to verify the effectiveness of the proposed controller.
Leukemia is a type of cancer that affects white blood cells. In this disease, immature blood cells undergo genetic mutations, leading to excessive replication and reduced cell death compared to healthy cells. In cancer, there may be the activation of oncogenes and the deactivation of tumor suppressor genes that control certain cellular functions. Despite the undeniable contribution to the patient's recovery, conventional cancer treatments may have some not-so-beneficial effects. In this case, gene therapy appears as an alternative to classical treatments. Gene therapy delivers genetic material to cells to replace or modify dysfunctional genes, a safe method for neoplasms. One of the types of nucleic acids explored in gene therapy is microRNA (miRNA), a group of endogenous, non-proteincoding, small single-stranded RNA molecules involved in the regulation of gene expression, cell division, differentiation, angiogenesis, migration, apoptosis, and carcinogenesis. This review aims to bring together the most recent advances found in the literature on cancer gene therapy based on microRNAs in the oncological context, focusing on leukemia.
The value of autologous bone marrow transplantation in the treatment of children with acute myeloid leukemia (AML) is unknown. We compared autologous bone marrow transplantation with intensive consolidation chemotherapy as treatments for children with AML in first remission.
We induced remission with one course of daunorubicin, cytarabine, and thioguanine, followed by one course of high-dose cytarabine (3 g per square meter of body-surface area for six doses). Patients in remission after the second course of induction therapy were eligible for randomization. Between June 1988 and March 1993, 552 of 649 enrolled patients who could be evaluated (85 percent) entered remission. A total of 209 patients were not eligible for randomization; of the remaining 343 patients, 232 were randomly assigned to receive six courses of intensive chemotherapy (117 patients) or autologous transplantation (115 patients). Of the original 649 patients, 189, including 21 with Down's syndrome, were nonrandomly assigned to receive intensive chemotherapy.
The rates of event-free survival and overall survival for the entire group at three years were 34 +/- 2.5 percent and 42 +/- 2.6 percent, respectively. For patients who were randomly assigned to one of the two treatment groups, the mean (+/- SE) rates of event-free survival three years after randomization were not significantly different in the two groups when examined by intention-to-treat analysis: 36 +/- 5.8 percent for the intensive-chemotherapy group as compared with 38 +/- 6.4 percent for the autologous-transplantation group; and the relative risk of treatment failure for the chemotherapy group as compared with the autologous-transplantation group was 0.81 (P = 0.20 by the log rank test; 95 percent confidence interval, 0.58 to 1.12). Overall survival at three years followed a similar pattern. There was a lower relapse rate (31 percent vs. 58 percent, P < 0.001) but a higher rate of treatment-related mortality (15 percent vs. 2.7 percent, P = 0.005) in the group treated with autologous transplantation than in the intensive-chemotherapy group. The event-free survival at three years for the nonrandomized intensive-chemotherapy group was 39 +/- 5.1 percent, and for a contemporaneous group of patients each of whom received a histocompatible bone marrow transplant from a sibling, it was 52 +/- 8.0 percent.
Treatment of children with AML in first remission with either autologous bone marrow transplantation or intensive chemotherapy prolongs event-free survival equally.
About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions.
We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment.
Of the 693 patients who had a complete remission, 596 were randomly assigned to receive postremission cytarabine. After a median follow-up of 52 months, the disease-free survival rates in the three treatment groups were significantly different (P = 0.003). Relative to the 100-mg group, the hazard ratios were 0.67 for the 3-g group (95 percent confidence interval, 0.53 to 0.86) and 0.75 for the 400-mg group (95 percent confidence interval, 0.60 to 0.94). The probability of remaining in continuous complete remission after four years for patients 60 years of age or younger was 24 percent in the 100-mg group, 29 percent in the 400-mg group, and 44 percent in the 3-g group (P = 0.002). In contrast, for patients older than 60, the probability of remaining disease-free after four years was 16 percent or less in each of the three postremission cytarabine groups.
These data support the concept of a dose-response effect for cytarabine in patients with AML who are 60 years of age or younger. The results with the high-dose schedule in this age group are comparable to those reported in similar patients who have undergone allogeneic bone marrow transplantation during a first remission.
with a median of 12 months for 7-3 and 27 months for 7-3-7 (P = .01). Survival appeared to be prolonged with 7-3-7 in patients aged less than 55 years, with a median of 9 months for 7-3 as compared with 17 months for 7-3-7 (P = .03). In older patients (aged 255 years), 7-3-7 was more toxic, with significantly more severe (World Health Organization (WHO) grade 3 or 41 stomatitis (P = .02) and no additional clinical benefit. Hematologic toxicity for induction courses was similar, with granulocytopenia t0.5 x 109/L for a median of 16 days per course for 7-3 and 15 days for 7-3-7. Hematologic toxicity was more severe for 5-2-5 consolidation courses (P = .003). Induc- tion and consolidation therapy intensified with etoposide resulted in significantly improved remission duration but not survival.
Several proteins that contribute to epigenetic mechanisms of gene regulation contain a characteristic motif of unknown function called the SET (Suvar3-9, Enhancer-of-zeste, Trithorax) domain. We have demonstrated that SET domains mediate highly conserved interactions with a specific family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). These include myotubularin, the gene of which is mutated in a subset of patients with X-linked myotubular myopathy, and Sbf1, a newly isolated homologue of myotubularin. In contrast with myotubularin, Sbf1 lacks a functional catalytic domain which dephosphorylates phospho-tyrosine and serine-containing peptides in vitro. Competitive interference of endogenous SET domain-dsPTPase interactions by forced expression of Sbf1 induced oncogenic transformation of NIH 3T3 fibroblasts and impaired the in vitro differentiation of C2 myoblast cells. We conclude that myotubularin-type phosphatases link SET-domain containing components of the epigenetic regulatory machinery with signalling pathways involved in growth and differentiation.
Optimization of remission-induction and postremission therapy in elderly individuals with acute myeloid leukemia (AML) was the subject of a randomized study in patients older than 60 years. Remission-induction chemotherapy was compared between daunomycin (DNR) 30 mg/m2 on days 1, 2, and 3 versus mitoxantrone (MTZ) 8 mg/m2 on days 1, 2, and 3, both plus cytarabine (Ara-C) 100 mg/m2 on days 1 to 7. Following complete remission (CR), patients received one additional cycle of DNR or MTZ chemotherapy and were then eligible for a second randomization between eight cycles of low-dose (LD)-Ara-C 10 mg/m2 subcutaneously every 12 hours for 1 2 days every 6 weeks or no further treatment.
A total of 242 patients was randomized to DNR and 247 to MTZ. Median age of both study groups was 68 years. Secondary AML was documented in 26% and 25% of patients in either arm. The probability of attaining CR was greater (P = .069) with MTZ (47%) than with DNR (38%). Median duration of neutropenia was 19 (DNR) and 22 days (MTZ). The greater response rate to MTZ therapy correlated with reduced occurrence of chemotherapy resistance (32% v 47%, P = .001). With a median follow-up of 6 years, 5-year disease-free survival (DFS) is 8% in each arm. Overall survival estimates are not different between the groups (6% v 9% at 5 yrs). Poor performance status at diagnosis, high WBC count, older age, secondary AML, and presence of cytogenetic abnormalities all had an adverse impact on survival. Secondary AML and abnormal cytogenetics predicted for shorter duration of CR. Among complete responders, 74 assessable patients were assigned to Ara-C and 73 to no further therapy. Actuarial DFS was significantly longer (P = .006) for Ara-C-treated (13% [SE = 4.0%] at 5 years) versus nontreated patients (7% [SE = 3%]), but overall survival was similar (P = .29): 18% (SE = 4.6%) versus 15% (SE = 4.3%). Meta-analysis on the value of Ara-C postremission therapy confirms these results.
In previously untreated elderly patients with AML, MTZ induction therapy produces a slightly better CR rate than does a DNR-containing regimen, but it has no significant effect on remission duration and survival. Ara-C in maintenance may prolong DFS, but it did not improve survival.
We have developed a restriction map of the chromosome 21 breakpoint region involved in t(8;21)(q22;q22.3) acute myelogenous leukemia (AML) and have isolated a genomic junction clone containing chromosome 8 and 21 material. Using probes from these regions, rearrangements have been identified in each of nine cases of t(8;21) AML examined. In addition, we have isolated cDNA clones from a t(8;21) AML cDNA library that contain fused sequences from chromosome 8 and 21. The chromosome 8 component, referred to as ETO (for eight twenty-one), is encoded over a large genomic region, as suggested by the analysis of corresponding yeast artificial chromosomes (YACs). The DNA sequence of the chromosome 21 portion of the fusion transcript is derived from the normal AML1 gene. A striking similarity (67% identity over 387 bp, with a corresponding 69% amino acid identity) was detected between AML1 and the Drosophila segmentation gene, runt. The critical consequence of the translocation is the juxtaposition of 5' sequences of AML1 to 3' sequences of ETO, oriented telomere to centromere on the der(8) chromosome.
The purpose of this study was to determine the relative merits of idarubicin and daunorubicin in acute myeloid leukemia (AML) therapy. Thirty-two sites provided 214 previously untreated adults with AML aged 15 years or more who were randomized to receive for induction therapy cytarabine 100 mg/m2/d as a continuous 7-day infusion plus either daunorubicin 45 mg/m2/d (A + D) or idarubicin 13 mg/m2/d (A + I), daily on the first three days of treatment. Postremission therapy consisted of two courses of the induction regimen at the same daily doses, with the anthracycline administered for 2 days and cytarabine for 5. The complete response (CR) rates for evaluable patients were 70% (A + I) and 59% (A + D) (P = .08). The difference in CR rates was significant in patients aged 18 to 50 years (88% for A + I, 70% for A + D, P = .035). Resistant disease was a significantly more frequent cause of induction therapy failure with A + D than with A + I. Hyperleukocytosis (white blood cell count greater than 50,000/microL) unfavorably affected the attainment of CR with A + D but not with A + I. CR duration was significantly greater after A + I. CR duration was significantly greater after A + I treatment, and the survival of all randomized patients treated with A + I was significantly better than that observed after A + D treatment (median 12.9 months v 8.7 months, respectively, P = .038). Toxicity of the two treatments was similar, although A + I patients experienced more prolonged myelosuppression during consolidation therapy, and a greater incidence of mild chemical hepatitis was observed in the A + I group. It is concluded that, at the doses and schedule used in this study, A + I is superior to A + D for induction therapy of AML in adults.
Treatment of cancer with the epipodophyllotoxins (etoposide and teniposide) has been linked to the development of acute myeloid leukemia (AML) in children and adults, but the factors that might influence the risk of this complication of therapy are poorly defined. We therefore assessed the importance of potential risk factors for secondary AML in 734 consecutive children with acute lymphoblastic leukemia who attained complete remission and received continuation (maintenance) treatment according to different schedules of epipodophyllotoxin administration.
Secondary AML was diagnosed in 21 of the 734 patients, in 17 of whom this complication was the initial adverse event. Prolonged administration of epipodophyllotoxin (teniposide with or without etoposide) twice weekly or weekly was independently associated with the development of secondary AML (P less than 0.01 by Cox regression analysis). The overall cumulative risk of AML at six years was 3.8 percent (95 percent confidence interval, 2.3 percent to 6.1 percent); but within the subgroups treated twice weekly or weekly, the risks were 12.3 percent (95 percent confidence interval, 5.7 percent to 25.4 percent) and 12.4 percent (95 percent confidence interval, 6.1 percent to 24.4 percent), respectively. In the subgroups not treated with epipodophyllotoxins or treated with them only during remission induction or every two weeks during continuation treatment, the highest cumulative risk was 1.6 percent (95 percent confidence interval, 0.4 percent to 6.1 percent). After adjustment for treatment frequency, there was no apparent relation between the total dose of epipodophyllotoxins and the development of secondary AML. The relative hazard of etoposide as compared with teniposide could not be determined.
The risk of epipodophyllotoxin-related AML depends largely on the schedule of drug administration. Other factors, including the cumulative dose of epipodophyllotoxin, radiotherapy, and the initial biologic features of the leukemic blast cells, do not appear to have critical roles.
4'-Demethoxydaunorubicin (idarubicin [IDR]) is a new anthracycline that differs from its parent compound by the deletion of a methoxy group at position 4 of the chromophore ring. This minor structural modification results in a more lipophilic compound with a unique metabolite that has a prolonged plasma half-life as well as in vitro and in vivo antileukemia activity. To determine its activity in acute myelogenous leukemia (AML), 130 consecutive adult patients between the ages of 16 and 60 with newly diagnosed disease were randomized in a single institution study to receive either IDR in combination with cytosine arabinoside (Ara-C) or standard therapy with daunorubicin (DNR) and Ara-C. The trial was analyzed using the O'Brien-Fleming multiple testing design that allowed for periodic inspection of the data at specific patient accession points. After accrual of 60 patients per arm, analysis showed that patients who received IDR/Ara-C had a superior response compared with those who received standard therapy: 48 of 60 patients (80%) achieved complete remission on the former arm compared with 35 of 60 patients on the latter (58%, P = .005). Logistic regression analysis of factors associated with complete response indicated that treatment with IDR/Ara-C offered a significant advantage to patients who presented with a high initial white blood cell count compared with treatment with DNR/Ara-C. The degree of marrow aplasia was approximately the same on each arm as was nonhematologic toxicity. Overall survival for patients on the IDR/Ara-C arm was 19.5 months compared with 13.5 months on the DNR/Ara-C arm (P = .025) at a median follow-up of 2.5 years. We conclude that IDR/Ara-C can effectively replace standard therapy with DNR/Ara-C in adult patients less than age 60 with newly diagnosed AML.
Previously untreated patients with acute nonlymphocytic leukemia (ANLL) aged 15 to 70 years were randomized to either cytosine arabinoside 100 mg/m2/d continuous intravenous (IV) infusion days 1 through 7, daunorubicin 50 mg/m2/d IV days 1 through 3 (7-3), or the same drugs intensified with etoposide 75 mg/m2/d IV days 1 through 7 (7-3-7) as induction therapy. Patients achieving complete remission (CR) received two courses of consolidation therapy (5-2 or 5-2-5) followed by maintenance therapy. Of 264 eligible patients, CR occurred in 56% of 7-3 and 59% of 7-3-7 patients; 7-3-7 significantly improved remission duration (P = .01). The median remission duration was 12 months for 7-3 and 18 months for 7-3-7. Survival was similar when the two arms were compared overall. Subset analysis performed to identify patients with the most benefit showed that etoposide significantly prolonged remission duration in younger patients (less than 55 years) with a median of 12 months for 7-3 and 27 months for 7-3-7 (P = .01). Survival appeared to be prolonged with 7-3-7 in patients aged less than 55 years, with a median of 9 months for 7-3 as compared with 17 months for 7-3-7 (P = .03). In older patients (aged greater than or equal to 55 years), 7-3-7 was more toxic, with significantly more severe [World Health Organization (WHO) grade 3 or 4] stomatitis (P = .02) and no additional clinical benefit. Hematologic toxicity for induction courses was similar, with granulocytopenia less than 0.5 x 10(9)/L for a median of 16 days per course for 7-3 and 15 days for 7-3-7. Hematologic toxicity was more severe for 5-2-5 consolidation courses (P = .003). Induction and consolidation therapy intensified with etoposide resulted in significantly improved remission duration but not survival.
Twenty-seven patients with refractory leukemia were treated with 1-beta-D-arabinofuranosylcytosine (ara-C), 0.3 to 3.0 g/m2 as i.v. infusions over 1, 2, 4, or 24 h. The pharmacokinetics of ara-C in plasma and its 5'-triphosphate (ara-CTP) in leukemic cells from peripheral blood were studied after a single infusion of 3 g/m2 over 2 h in 13 patients. Accumulation of ara-CTP in leukemic cells remained linear until 1 to 2 h after the infusion. At the time when the rate of ara-CTP accumulation deviated from linearity, the plasma concentration of ara-C was 5- to 20-fold lower [8.1 +/- 4.4 (SD) microM] than the steady-state level during the infusion. Plasma ara-C and cellular ara-CTP pharmacokinetics were studied after two serial infusions in 14 additional patients. Varying the duration of infusion of an ara-C dose between 1, 2, and 4 h (corresponding to infusion rates of 3000, 1500, and 750 mg/m2/h) did not substantially change the rate of ara-CTP accumulation by leukemic cells. The peak ara-CTP concentration and the area under the concentration times time curve (AUC) of ara-CTP in leukemic cells increased with prolongation of the infusion. Although steady-state concentration of ara-C and AUC of ara-C in plasma were proportionally reduced by 1.0 or 0.5 g/m2 infusion over 2 h, ara-CTP accumulation rate and AUC in leukemic cells did not change compared with administration of 3 g/m2 over 2 h. However, when the infusion rate was further reduced to 0.4 or 0.3 g/m2 over 2 h, resulting in steady-state plasma ara-C concentrations of less than 7 microM, the accumulation rate of ara-CTP was substantially reduced as was the ara-CTP intracellular AUC. The cellular elimination rate of ara-CTP remained constant under all infusion conditions. These findings support the conclusion that high-dose ara-C therapy, as currently administered, results in plasma ara-C concentrations that saturate the accumulation of ara-CTP by circulating leukemic cells. We recommend that intermediate dose rates, 200 to 250 mg/m2/h, be evaluated in future studies as an alternative to the substantially higher ara-C dose rates currently in use.
This article describes three patients with megakaryoblastic leukemia, in whom the blast cells were identified as megakaryoblasts by the platelet peroxidase (PPO) reaction. More than 70% of the blasts in these patients were positive for the PPO reaction. Ultrastructurally, acid phosphatase activity in the megakaryoblasts was detected in the nuclear envelope, the endoplasmic reticulum, and in a few granules, but not in the Golgi cisternae. Some blast cells were identified by immunofluorescence or immunoalkaline phosphatase, using monoclonal antiplatelet glycoprotein IIb/IIIa antibody. In one patient, most of the blasts were positive for anti-HLA-DR monoclonal antibody. The possible order of the appearance of markers in the maturation of the megakaryocytic cell lineage is postulated, based on the data from the present cases and those previously reported. PPO activity appears in very immature cells, which retain Ia-like antigens. Platelet-specific glycoprotein IIb/IIIa is seen in immature cells that are only recognized by PPO activity.
A collaborative overview, using individual patient data, has been performed to compare idarubicin versus daunorubicin or other anthracyclines, when used with cytosine arabinoside as induction chemotherapy for newly diagnosed acute myeloid leukaemia. There were 1052 patients in five trials versus daunorubicin, 100 in one trial versus doxorubicin; and 745 in one trial versus zorubicin. In the trials of idarubicin versus daunorubicin, early induction failures were similar with the two treatments (20% idarubicin v 18% daunorubicin; P = 0.4), but after day 40 the later induction failures were fewer with idarubicin (17% v 29% P< 0.0001). Therefore complete remission rates were higher with idarubicin (62% v 53%; P=0.002). Among remitters, fewer of the patients allocated to idarubicin relapsed (P=0.008) but slightly more died in remission, leading to a non-significant benefit (P = 0.07) in disease-free survival. Overall survival in these five trials was significantly better with idarubicin than with daunorubicin (13% v 9% alive at 5 years; P = 0.03). There was a trend (P = 0.006 for remission rate) for the benefit of idarubicin over daunorubicin to decrease with increasing age. There were no significant differences in outcome in the small trial comparing idarubicin versus doxorubicin, or in the large trial comparing idarubicin versus zorubicin. The induction regimens based on idarubicin achieved, in the particular circumstances of the trials reviewed here, better remission rates and better overall survival than those based on daunorubicin.
1957 allogeneic HLA-identical sibling-donor bone-marrow transplants done in 52 European centres between 1979 and 1986 and reported to the European bone-marrow transplant leukaemia registry were analysed. The most important factor influencing leukaemia-free survival, transplant-related mortality, and relapse incidence was the stage of the disease at the time of the transplant. This dominant role of the stage of the disease in all three diagnostic categories - acute myeloblastic leukaemia, acute lymphoblastic leukaemia, and chronic myeloid leukaemia - for all three end-points clearly indicates that resistance of the leukaemia cell to the procedure is more important than bulk of the disease. Additional prognostic factors for leukaemia-free survival and transplant-related mortality were age of the patient, cyclosporin for preventing graft-versus-host disease, and the donor-recipient sex combination. The risk of relapse was highest in patients with acute lymphoblastic leukaemia. In a multivariate analysis leukaemia-free survival was similar for all three major diagnostic categories and has not changed since the introduction of the European registry in 1979. These results show that the biological differences between the three main diagnostic categories of leukaemia are not as great as had been assumed and that the traditional approaches to improving results in recent years have failed.
Background: Following an induction chemotherapy, patients achieving a complete remission receive a first intensive consolidation course. Then, this is followed by allogeneic bone marrow transplantation if an HLA identical donor can be located (allo-BMT), while others are randomised to a second consolidation chemotherapy or autologous bone marrow transplantation (ABMT). If there is no clear survival benefit for either of these, other end points like disease free survival, treatment related morbidity and the costs of treatment will be given more importance.Methods: This is a retrospective analysis based on the EORTC AML 8 study, opened in june '93 and closed in june '94, comparing the three treatments mentioned. The case report forms of the clinical trial contained the following variables of relevance for an assessment of resource utilisation: number of days hospitalised, number of days in protected environment, supportive care given (eg transfusions, use of antibiotics), number of infectious episodes, number of days with fever. The cost calculations will be based on the resource utilisation data from the trial and unit prices (charges) from the Belgian health insurance and reimbursement system.Results: 941 patients entered the AML 8 study. 576 entered and remained into complete remission after induction and first intensive consolidation. Out of these, 137 with an HLA identical sibling were allografted, the other patients were randomised between ABMT (N = 117) and second intensive chemotherapy (N = 112). There were no differences between the alternatives with respect to overall survival, while for disease free survival and relapse risk allo-BMT was most favorable, followed by ABMT and chemotheraphy in that order. Treatment related morbidity was smallest for chemotherapy. This preliminary analysis contains only a comparison of resource utilisation. For all types of resource utilisation, the consumption was smallest for second intensive consolidation. Regarding the two types of BMT, none is uniformly most demanding: number of hospital days for allo-BMT patients is about 9% higher as the number for ABMT, while the number of transfusions is 40% higher for ABMT.Discussion: No valuation of outcomes has been attempted in this analysis, which is only concerned with some -important - elements of direct costs. As in all retrospective analyses, some important variables have not been included because of lack of data. Notably, for allo-BMT the costs of locating an HLA identical sibling has not been included as main endpoint in the AML 8 trial. Another issue that has not been included is the prevention or/and treatment of graft versus host disease (GVHD); this will be an important item in the planned cost evaluation, since we know that despite prevention for almost all patients eligible for allo-BMT, +/- 60% of the allografted patients had GVHD and half of these were actually treated for this.
The nature of the cells in 21 cases of acute leukaemia with blasts which were undifferentiated by light microscopy criteria was investigated by immunophenotyping, ultrastructural cytochemistry and DNA analysis. Two groups of cases were recognized. Fourteen cases were negative with B and T lymphoid markers and expressed one or two myeloid antigens detected by the monoclonal antibodies (McAb) MCS2 (CD13) and MY9 (CD33). Peroxidase activity was demonstrated at ultrastructural level by the method of Roels on unfixed cells in eight out of 10 cases; rearrangement of the immunoglobulin (Ig) genes was demonstrated in one of the three cases investigated. These cases are proliferations of early, MO, myeloblasts which can only be recognized by immunological and ultrastructural cytochemical methods. The remaining seven cases revealed a complex phenotype with expression of myeloid and lymphoid antigens. Peroxidase activity was detected in blasts from two cases with rearrangement of the Ig-heavy chain gene: in one of them the T cell receptor β and γ chain genes were also found in rearranged configuration. This group comprises cases of biphenotypic and mixed acute leukaemia which probably involve multipotent stem cells. This study demonstrates that the expression of myeloid antigens on blast cells parallels closely the presence of peroxidase activity and that lymphoid markers correlate with gene rearrangements at DNA level. Our findings are reassuring with respect to the specificity of the antimyeloid McAb for the diagnosis of cases which are unclassifiable by conventional methods.
Four patients with acute myeloid leukemia (AML) were treated with high-dose cyclophosphamide and total body irradiation followed by reinfusion of a portion of their own bone marrow collected during remission. This procedure was applied when the patients were in complete remission. They did not receive further maintenance chemotherapy after grafting. The use of bone marrow for grafting that had been pre-exposed to high-dose chemotherapy for remission induction did not preclude good hematologic regeneration. All patients showed stable remission that lasted for 64+, 21, 40+, and 19+ months, respectively. Death in the second patient was due to a medullary relapse of the leukemia. Autologous bone marrow transplantation in patients with AML in remission may permit lasting remissions, even when applied without additional chemotherapy and attempts to purify the marrow of neoplastic cells.
359 eligible children with acute myeloid leukaemia (AML) entered the MRC AML 10 trial between May 1988 and March 1995. Patients received four courses of intensive induction and consolidation chemotherapy, with or without subsequent autologous (A-BMT) or allogeneic (allo-BMT) bone marrow transplant. There were randomized comparisons of thioguanine versus etoposide in induction and of A-BMT versus not. Allo-BMT was recommended for patients with a HLA-matched sibling and was evaluated by donor versus no donor comparison. The complete remission rate was 92%. In first remission there were 20 deaths during consolidation chemotherapy and 11 after BMT (8/61 allo-BMTs, 1/60 A-BMTs and 2/4 matched unrelated donor transplants). The relapse rate was low, decreasing from 26% in the first year to 2% in the fourth. Long-term outcome was excellent with survival at 7 years from entry of 56% and event-free survival of 48%. There were no significant differences between thioguanine and etoposide, whereas both A-BMT and allo-BMT reduced relapse risk but did not produce a significant survival benefit. It appears that over half the children entered into AML 10 are cured, a result which compares favourably with other reported series. We conclude that four courses of intensive chemotherapy are an effective approach to the treatment of paediatric AML, which avoids the acute toxicity and long-term side-effects of BMT and also avoids the need for prolonged maintenance therapy or cranial irradiation.
Acute promyelocytic leukaemia (APL) is characterised by a unique fusion transcript, PML/ RARα. We tested for this transcript in 35 APL patients who were in apparent remission after various treatments. 11 of 13 patients who tested positive 4 months after achieving remission were in relapse 1-4 months later. All 22 patients who tested negative at 4 months were disease-free after a further 3 months to five years. The test may therefore prove useful in determining the need for additional treatment during clinical remission.
Older age is a poor prognosis factor in acute myeloid leukemia (AML). This double-blind trial was designed to test the hypothesis that granulocyte colony-stimulating factor (G-CSF) used as supportive care could improve the treatment of elderly AML patients. Two hundred thirty-four patients 55 or more years of age with a morphologic diagnosis of de novo or secondary AML, French-American-British (FAB) M0-M7, excluding M3, were randomly assigned to a standard induction regimen (daunorubicin at 45 mg/m2 intravenously [IV] on days 1 through 3 and Ara-C at 200 mg/m2 IV continuous infusion on days 1 through 7) plus either placebo or G-CSF (400 microg/m2 IV over 30 minutes once daily). Results are reported here for 211 centrally confirmed cases of non-M3 AML. The two groups were well balanced in demographic, clinical, and hematological parameters, with median ages of 68 years in the G-CSF and 67 years in the placebo groups. The complete response (CR) rate was not significantly better in the G-CSF group: 50% in the placebo and 41% in the G-CSF group (one-tailed P = .89). Median overall survival was also similar, 9 months (95% confidence interval [CI], 7 to 10 months) in the placebo and 6 months (95% CI, 3 to 8 months) in the G-CSF arms (P = .71). We found a significant 15% reduction in the time to neutrophil recovery in the G-CSF group (P = .014). G-CSF had no impact on recovery from thrombocytopenia (P = .80) or duration of first hospitalization (P = .27). When infection complications were evaluated, G-CSF had a beneficial effect on the duration but not on incidence of infection. G-CSF patients had fewer days with fever and shorter duration of antibiotic use. However, there was no difference in the frequency of total documented infections or in the number of fatal infections (19% placebo v 20% G-CSF). In this study of elderly AML patients, G-CSF improved clinical parameters of duration of neutropenia and antibiotic use, but did not change CR rate or survival or shorten hospitalization.
The complete remission (CR) rate after intensive chemotherapy for acute myelogenous leukemia (AML) remains low in elderly patients, mainly because of a higher infectious mortality rate related to neutropenia and an increased incidence of adverse prognostic factors. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to potentially recruit leukemic blasts into cell cycle and improve cytotoxic effects when given during chemotherapy, and to shorten the duration of neutropenia when administered after chemotherapy. Two hundred forty patients aged 55 to 75 years who had newly diagnosed AML were randomly assigned to receive placebo or Escherichia coli-derived GM-CSF (5 micrograms/kg/d by 6-hour intravenous infusion) starting during induction chemotherapy on day 1 and continued through and after chemotherapy until recovery of neutrophils, or evidence of regrowth of leukemia, or up to day 28. Induction chemotherapy consisted of idarubicin (8 mg/m2/d on days 1 to 5) and cytarabine (100 mg/m2/d on days 1 to 7). The study drug was not administered subsequent to the induction course. Patients who achieved a CR received continuous maintenance therapy for 1 year with four quarterly reinduction courses; in the 55- to 64-year age subgroup, patients were randomly assigned to receive or not a consolidation course before maintenance therapy. The CR rate was similar in the GM-CSF and placebo groups (63% and 60.5%, respectively; P = .79). The mortality, rate of resistant disease, and rate of regrowth of leukemia were also similar in both groups. The time to neutrophil recovery was shorter in patients who received GM-CSF (24 v 29 days; P = .0001), but the incidence and characteristics of infectious events were not different. The 2-year disease-free survival (DFS) rate was significantly improved in the GM-CSF group (48% v 21% in the placebo group; P = .003). This effect was highly significant in the cohort of patients aged 55 to 64, but only marginal in patients >/=65 years of age. There was a trend toward a longer overall survival (OS) in the GM-CSF group (P = .082). In summary, the administration of GM-CSF, concomitantly with chemotherapy and thereafter during induction course in AML, shortened the time to neutrophil recovery, but did not improve the CR rate in patients aged 55 to 75. Nonetheless, DFS and OS were significantly prolonged in patients aged 55 to 64 treated with GM-CSF. These results are promising and further evaluation of myeloid growth factors in AML is warranted.
Three strategies are used to prevent relapse in patients with acute myeloid leukaemia in first remission. Most of those with suitable donors are offered allogeneic haemopoietic-stem-cell transplant. Other patients may receive intensive chemotherapy or autologous transplantation; we undertook this randomised prospective trial to assess which is the better option.
After three courses of intensive chemotherapy, bone marrow was harvested from patients (<56 years of age) in remission who lacked an HLA-matched sibling donor. These patients were then randomised to receive, after one more course of chemotherapy, no further treatment (n=191) or an autologous bone-marrow transplant (BMT) after preparation with cyclophosphamide and total-body irradiation (n=190). Outcome comparisons were by intention to treat with adjustment for the most important risk factors for relapse.
381 patients were randomised (38% of those eligible). Of the 190 patients allocated autologous BMT, 126 received it. On intention-to-treat analysis the number of relapses was substantially lower in the autologous BMT group than in the group assigned no further treatment (64/190 [37%] vs 101/191 [58%], p=0.0007), resulting in superior disease-free survival at 7 years (53 vs 40%; p=0.04). These benefits were observed in all risk groups and age-groups. There were more deaths in remission in the autologous BMT group than in the no further treatment group (22 [12%] vs 7 [4%], p=0008). In children (<15 years) and patients with good-risk disease, survival from relapse in the no further treatment group was 35% and 38% at 2 years. There was an overall survival advantage in the autologous BMT group at 7 years (57 vs 45%, p=0.2).
The addition of autologous BMT to four courses of intensive chemotherapy substantially reduces the risk of relapse in all risk groups, leading to improvement in long-term survival. The good chance of salvage for children or patients with good-risk disease who relapse from chemotherapy, and the mortality, morbidity, late effects, and expense of autologous BMT, suggest that delay of autograft until second remission in these two groups may be appropriate.
A uniform system of classification and nomenclature of the acute leukaemias, at present lacking, should permit more accurate recording of the distribution of cases entered into clinical trials, and could provide a reference standard when newly developed cell-surface markers believed to characterize specific cell types are applied to cases of acute leukaemia. Proposals based on conventional morphological and cytochemical methods are offered following the study of peripheral blood and bone-marrow films from some 200 cases of acute leukaemia by a group of seven French, American and British haematologists. The slides were examined first independently, and then by the group working together. Two groups of acute leukaemia, 'lymphoblastic' and myeloid are further subdivided into three and six groups. Dysmyelopoietic syndromes that may be confused with acute myeloid leukaemia are also considered. Photomicrographs of each of the named conditions are presented.
The doxorubicin-selected lung cancer cell line H69AR is resistant to many chemotherapeutic agents. However, like most tumor
samples from individuals with this disease, it does not overexpress P-glycoprotein, a transmembrane transport protein that
is dependent on adenosine triphosphate (ATP) and is associated with multidrug resistance. Complementary DNA (cDNA) clones
corresponding to messenger RNAs (mRNAs) overexpressed in H69AR cells were isolated. One cDNA hybridized to an mRNA of 7.8
to 8.2 kilobases that was 100- to 200-fold more expressed in H69AR cells relative to drug-sensitive parental H69 cells. Overexpression
was associated with amplification of the cognate gene located on chromosome 16 at band p13.1. Reversion to drug sensitivity
was associated with loss of gene amplification and a marked decrease in mRNA expression. The mRNA encodes a member of the
ATP-binding cassette transmembrane transporter superfamily.
A randomized clinical trial was undertaken to compare the therapeutic effectiveness of idarubicin (IDR) to daunorubicin (DNR), and both were given in combination with cytarabine (CA) in acute myelogenous leukemic (AML) patients.
Newly diagnosed patients were given a daily infusion of CA (100 mg/m2) for 7 days and were assigned randomly to receive DNR (45 mg/m2) or IDR (12 mg/m2) daily for the first 3 days. Those patients who achieved a complete remission (CR) were given three consolidation courses that consisted of CA (100 mg/m2 intravenously [IV]) and thioguanine (TG; 100 mg/m2 orally) every 12 hours for 5 days and either DNR (50 mg/m2) or IDR (15 mg/m2) on the first day of each cycle. After consolidation, patients received late intensification, which consisted of the same drugs used for induction except that the CA was given for 5 days and the anthracycline for 2 days. Four courses were planned at 13-week intervals.
The CR rates were 75 of 105 (71%) on the IDR arm and 65 of 113 (58%) on the DNR arm (P = .03). The median survival and median remission durations were 297 and 433 days, respectively, on the IDR arm. The median survival and median remission durations were 277 and 328 days, respectively, on the DNR arm. Six deaths occurred during late intensification, five on IDR and one on DNR; this approach was abandoned after 47 patients were entered. The median survival was significantly longer for patients who received late intensification.
This trial demonstrated that IDR was more effective than DNR in remission induction in AML.
We describe a form of acute myeloid leukaemia (AML), designated AML-MO, with minimal myeloid differentiation, not included previously in the FAB classification. AML-MO cannot be diagnosed on morphological grounds alone as the blast cells are large and agranular, sometimes resembling L2 or, rarely, L1 lymphoblasts, and should be identified by the following features: negative myeloperoxidase (MPO) and Sudan Black B reaction (or positive in less than 3% of blasts), negative B and T lineage markers and expression of myeloid antigens recognized by at least one monoclonal antibody, CD13 or CD33. Other myeloid markers are also often positive and these include CD11b and the enzyme MPO demonstrated by immunocytochemistry and/or electron microscopy analysis. The findings in a group of 10 cases satisfying the criteria for AML-MO are described. AML-MO represents 2-3% of all cases of AML and 1-1.5% of all acute leukaemias. Its clinical and biological significance is not yet apparent but its identification in a larger number of cases may achieve this aim.
The t(8;21)(q22;q22) translocation is a non-random chromosomal abnormality frequently found in patients with acute myeloid leukemia (AML) with maturation (M2 subtype). We report here the cloning of a gene, named AML1, on chromosome 21 that was found to be rearranged in the leukemic cell DNAs from t(8;21) AML patients. The breakpoints in 16 out of 21 patients were clustered within a limited region of AML1, and detailed analysis in 3 patients revealed that the breakpoints occurred in the same intron of the gene. Sequencing of cDNA clones identified a long open reading frame encoding a 250-amino acid protein. Northern blot analysis detected four constant mRNA species in t(8;21) leukemic and normal cells; the largest species was more abundant in the leukemic cells than in normal cells. In addition, two mRNA species limited to the leukemic cells were found. These findings indicate that the AML1 gene may be involved in neoplastic transformation of AML with the t(8;21) translocation.
A highly increased risk of myelodysplasia (MDS) and acute myeloid leukemia (AML) has been demonstrated following therapy with alkylating agents. The risk increases with cumulative dose and with the age of the patient. Most cases of MDS and AML following therapy with alkylating agents present chromosome aberrations, primarily loss of whole chromosomes No. 5 and/or No. 7 or various parts of the long arms of these chromosomes. The risk of MDS and AML following high-voltage radiotherapy is much lower. Recently an increased risk of AML has been demonstrated following therapy with the epipodophyllotoxins etoposide and teniposide. These leukemias typically present without preceding MDS and often show balanced aberrations of chromosome bands 11q23 and 21q22.
The median latency of 2 degrees MDS/AL is 4 to 5 years. A high percentage of patients with 2 degrees MDS/AL convert to 2 degrees AL. Survival of either is less than 1 year. A constellation of morphologic abnormalities from all 3 cell lines produces a unique appearance. Both 2 degrees MDS and 2 degrees AL are difficult to classify by the FAB system. With the exception of the identification of karyotypic abnormalities, the biology of 2 degrees MDS/AL remains largely unexplored. Alterations of chromosomes 5 and 7 predominate, but other associated cytogenetic abnormalities are being increasingly recognized. A synthesis of data regarding 2 degrees MDS/AL resulting from the treatment of several primary malignancies generates the tentative conclusions that (a) many of the alkylating agents, and the nonclassic alkylating agent procarbazine, are leukemogens; (b) melphalan is a more potent leukemogen than cyclophosphamide. None of the other alkylating agents has been clearly established to be more or less potent than another; (c) increasing duration or amount of alkylator-based chemotherapy increases the risk of leukemogenesis; (d) low doses of radiation delivered to large volumes of bone marrow are weakly leukemogenic. High doses of radiation delivered to small volumes are not. Due to the latter, there is minimal additive risk for 2 degrees MDS/AL among studies using alkylator-based chemotherapy and radiotherapy, either concurrently or sequentially; (e) the older patient (greater than 40) is at increased risk for 2 degrees MDS/AL, at least in Hodgkin's disease. Children may be at lesser risk than adults, and younger children at lesser risk than older children; (f) the risk of 2 degrees MDS/AL peaks within the first decade after treatment for the primary malignancy. The incidence rates during the second decade are low. Identified occupational/environmental risks for 2 degrees MDS/AL include benzene, ambient and diagnostic radiation exposure, and perhaps ethylene oxide. The similarities in karyotype abnormalities among leukemic cells of those whose occupations expose them to chemical hazard, and those who are exposed to cytotoxic agents, suggest that many more environmental leukemogens have yet to be discovered. Karyotype is an important prognostic factor for both achievement of CR and for survival. Nonaggressive treatment approaches have not proven useful, although the use of hematopoietic growth factors offers promise in this area. Combination chemotherapy is justified in patients with adequate performance statuses and "favorable" karyotypes. Allogeneic bone marrow transplantation is currently the only curative approach, and can be applied without attempts to first reduce the leukemic burden.
Fifty-nine European teams have reported 919 autografts for the consolidation of acute myelocytic leukemia (AML) up to December 31, 1989. The distribution for autologous bone marrow transplantation (ABMT) was 671 in first complete remission (CR1) and 196 in CR2. Pretransplantation regimes were: total-body irradiation (TBI), 456; busulfan plus cyclophosphamide (BU-CY) 174; marrow purging with mafosfamide, 269 (corresponding to 26% of all patients in CR1 and 41% in CR2). Patients autografted in CR1 with no high risk factor (standard risk) had a leukemia-free survival (LFS) and relapse rate at 7 years of 48 +/- 2 and 41 +/- 3%, respectively. Of all the prognostic factors studied, only secondary leukemia was correlated with a poorer LFS (19 +/- 9% at 1 year) and a higher relapse rate (76 +/- 11%) (p less than 0.0001). For patients autografted in CR2, the LFS and relapse rate were 34 +/- 4 and 54 +/- 5%. With the restriction of a shorter follow-up, the results achieved with the BU-CY combinations (LFS and relapse rate at 3 years, CR1 47 +/- 6 and 45 +/- 7%; CR2, 37 +/- 9 and 50 +/- 10%) did not differ from those with TBI or other chemotherapy combinations. LFS and relapse rates were correlated with several pretransplant intervals: in CR1, patients reaching CR more rapidly (less than or equal to 40 days) had a better LFS (53 +/- 3 versus 42 +/- 3%; p = 0.03) and a lower relapse rate (46 +/- 3 versus 57 +/- 3%; p = 0.03). In patients autografted less than 3 months, 3-6 months and more than 6 months after CR, the LFS was 26 +/- 5, 49 +/- 3, and 55 +/- 4%, respectively, and the relapse rates 63 +/- 5, 38 +/- 3, and 36 +/- 4% (p less than 0.0001 for both). In CR2, patients autografted more than 18 months after the initial diagnosis had a better LFS (42 +/- 5 versus 24 +/- 5%; p less than 0.001) and a lower relapse rate (45 +/- 6 versus 65 +/- 6%; p less than 0.001). For those autografted less than 3 months, 3-6 months and more than 6 months after CR, the probability of LFS was 30 +/- 5, 30 +/- 7, and 50 +/- 9% (p = 0.06), respectively and the relapse rates 63 +/- 6, 50 +/- 8, and 36 +/- 8% (p = 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)
The need for reproducibility in the classification of acute leukaemia has made it necessary to incorporate information derived from new techniques which have become essential for the study of these disorders. In addition to classic morphology and cytochemistry (FAB proposals), it is necessary to add immunology and cytogenetics (MIC proposals), as well as to investigate further the biological and diagnostic significance of molecular events. As a result of these investigations a new group of leukaemias merit recognition as distinct entities. These include three types of ALL with specific chromosome abnormalities, namely, i) t (9;22), ii) t (4;11) and iii) t (1;19) and four subtypes of AML, i) with minimal differentiation or AML-M0, ii) with basophilic precursors or M2Baso, iii) AML (M4/M5) with t (8;16) and iv) AML with trilineage myelodysplasia. Biphenotypic acute leukaemia constitutes also a distinct entity with features of ALL and AML and represents a malignancy probably affecting multipotent stem cells. We propose an objective evaluation system for biphenotypic leukaemias based on a score in which the various lineage markers are graded according to their known specificity.
This phase III, randomized trial in previously untreated adults with ANLL compared mitoxantrone plus cytosine arabinoside with the CALGB "7 + 3" daunorubicin-based regimen. Two hundred evaluable patients (98 treated with the mitoxantrone-based regimen and 102 with the daunorubicin-based regimen) were included in the analysis of efficacy. The median age of the patients was 60 years. The induction regimen comprised cytosine arabinoside 100 mg/m2 by infusion daily for 7 days and mitoxantrone 12 mg/m2 or daunorubicin 45 mg/m2 daily for days 1-3. If needed, a second induction course was administered: cytosine arabinoside for 5 days and mitoxantrone or daunorubicin for 2 days. Postremission therapy consisted of two consolidation courses, identical to the second induction course. Sixty-three percent (62 of 98) of patients treated with mitoxantrone achieved complete remission (CR), compared to 53% (54 of 102) treated with daunorubicin. The median time to CR was 35 days in patients treated with mitoxantrone and 43 days for those treated with daunorubicin. Eighty-nine percent (55 of 62) of patients treated with mitoxantrone who entered complete remission achieved CR following one induction course, compared to 68% (37 of 54) of patients treated with daunorubicin who entered CR. The median duration of CR was 240 days in patients treated with mitoxantrone and 198 days in those treated with daunorubicin; the median length of survival was 328 days in patients who received mitoxantrone and 247 days in those who received daunorubicin. The toxicity profiles in patients treated with either of the two regimens were comparable in incidence and in severity. Patients treated with mitoxantrone required fewer median platelet units and were treated with fewer median days of intravenous antibiotics, compared to those who received daunorubicin. Mitoxantrone in combination with cytosine arabinoside is effective in previously untreated ANLL. complete remissions occur more frequently after a single induction course of the mitoxantrone-based regimen, compared to the standard Cancer and Acute Leukemia Group B regimen. This should be explored in further trials.
Recent investigations have suggested a role for marrow ablative chemotherapy and radiotherapy given with autologous bone marrow transplantation (auto-BMT) in the treatment of acute myeloid leukemia (AML), but prospective studies have not been reported. We assessed the comparative values of auto-BMT and allogeneic marrow transplantation (allo-BMT) in 117 15- to 60-year-old consecutive patients (median, 43 years) with AML following remission-induction therapy. In 32 cases of the 90 (77%) complete responders, auto-BMT (nonpurged) was undertaken at a median of 3.8 months and in 23 eligible cases human leukocyte antigen (HLA)-matched allo-BMT occurred at 3.0 months after attainment of remission. Thus, nearly 60% of complete responders had access to transplantation, the others being withdrawn because of relapse, refusal, or other causes. Median time of regeneration to neutrophils 0.5 x 10(9)/L and platelets 20 x 10(9)/L were 39 and 63 days following auto-BMT versus 21 and 19 days after allo-BMT, respectively. AML relapse was the predominant cause of failure after auto-BMT (17 of 32) and procedure-related death was seen in three of 32 patients. The actuarial rates of relapse at 3 years are 60% (auto-BMT) and 34% (allo-BMT) (log-rank, P = .03). Patients treated with auto-BMT and allo-BMT have an overall survival of 37% and 66% at 3 years posttransplant, respectively (P = .05). Relapse-free 3-year survival rates are 35% and 51%, respectively (P = .12). Survival of the nongrafted complete responders is less than 10%. This study shows that allo-BMT in adult patients with AML in first complete remission (CR) results in more rapid hematopoietic reconstitution, is followed by fewer recurrences, and provides better survival than auto-BMT.
For the diagnosis of M7, the bone marrow aspirate shows a leukemic cell infiltrate that comprises 30% or more of all cells. These cells are identified as being of megakaryocyte lineage by the platelet peroxidase reaction on electron microscopy or by tests with monoclonal or polyclonal platelet-specific antibodies. Myelofibrosis or increased bone marrow reticulin are a prominent aspect in most patients with M7. In patients with increased reticulin, the bone marrow sample may be difficult to obtain and the counts done on the marrow films may be misleading. In these patients, the diagnosis of M7 should be based on excellent bone marrow biopsy sections that show an excess of blasts and, at times, increased numbers of maturing megakaryocytes; and on the presence of unequivocal megakaryoblasts in the peripheral blood or bone marrow (or both) as shown by immunologic techniques.
We report the results of a prospective study in patients more than 65 years of age in whom two different therapeutic strategies were compared: immediate intensive-induction chemotherapy (arm A) versus "wait and see" and supportive care and mild cytoreductive chemotherapy only for relief of progressive acute myeloid leukemia (AML)-related symptoms (arm B). The major objective of the study was to compare survival outcome of both regimens. Thirty-one patients on arm A received one or two courses of daunorubicin, vincristine, and cytarabine for remission induction followed by one additional cycle for consolidation in case of complete remission (CR). Among 29 patients on arm B, cytoreductive chemotherapy (hydroxyurea, cytarabine) had to be initiated for palliation of leukemia-associated complications in 21 patients at a median of 9 days after diagnosis. Overall survival duration for patients treated on arm A was significantly (P = .015) longer than the survival in arm B (median survival, 21 weeks v 11 weeks; projected survival at 2.5 years, 13% v 0%). Eighteen (58%) of arm A patients and none (0%) of arm B patients entered CR. Of the first group, projected disease-free survival at 2 years is 17%. The median percentages of days spent in the hospital by arm A and B patients were 55% and 50%, respectively. This study shows that a strategy based on modern supportive care and a wait and see approach yields extremely poor results. It is not superior in regard to the frequency of hospital admission and is inferior regarding survival outcome.
An analysis was conducted of clinical and laboratory variables associated with response to remission induction therapy and remission duration in 440 patients with acute myelogenous leukemia treated between 1975 and 1983. The complete remission rate was 259/440 (59%). Specific cytogenetic abnormalities such as t(8;21), t(15;17), and inv16 were found to be favorable for response to therapy and/or remission duration, whereas those with a normal (diploid) karyotype had an intermediate prognosis. All other karyotypic abnormalities were associated with lower response rates and short complete remission durations. The karyotypes were classified as favorable, intermediate, and unfavorable groups for response and remission duration after allowing for all the other observed clinical and laboratory values related to prognosis. The cytogenetic classification was prospectively validated in an independent test group of 130 patients treated between 1983 and 1986 and showed a consistent relationship to response and remission duration. Logistic regression and proportional hazard models developed from the initial 440 patients were prospectively evaluated in the test group of 130 patients. Clear stratifications of patients into good, intermediate, and poor risk groups were obtained in the prospective tests. The karyotype of the leukemia cells is an independent prognostic variable for response and remission duration in acute myelogenous leukemia.
The results are presented of allogeneic transplantation for 363 patients with acute non-lymphoblastic leukemia treated in Seattle from May 1973 through December 1985. The probabilities of surviving disease-free for 5 years for patients transplanted in first remission, in second remission, in untreated first relapse or in chemotherapy-resistant first relapse were 46%, 28%, 30%, and 21%, respectively. The corresponding probabilities of relapse within 5 years were 25%, 37%, 36% and 56%, respectively. Prognostic factors predictive of survival after marrow transplantation for patients transplanted in first remission included age, donor sex and the number of circulating blasts at the time of diagnosis. Acute graft-versus-host disease (GVHD) had a major adverse effect on survival, but chronic GVHD decreased the risk of relapse for patients transplanted in first remission.
In a prospective controlled trial, the relative effectiveness of allogeneic bone marrow transplantation and postremission chemotherapy was assessed for adult patients with acute myelogenous leukemia in first complete remission. Twenty-three patients, 15 to 45 years of age, who had an HLA-identical sibling donor were designated to receive bone marrow transplantation. Forty-four patients who either lacked an HLA-identical sibling or were over 45 years of age were designated to receive intensive consolidation chemotherapy. The actuarial rate of leukemia relapse was significantly lower in the transplantation group than in the chemotherapy group (40 +/- 25% [95% confidence interval] compared with 71 +/- 14%, p = 0.01). Actuarial survival at greater than 4 years was not significantly different (40 +/- 21% compared with 27 +/- 14%, p greater than 0.4). These data show that bone marrow transplantation is more effective than consolidation chemotherapy in preventing leukemia relapse, but overall survival was not improved in this study.
Twelve consecutive patients aged 18-53 were given autologous remission bonemarrow and cyclophosphamide and total-body irradiation to maintain first remission of acute myeloid leukaemia. Follow-up lasted at least 6 months. Seven patients remain in complete unmaintained remission 26-140 weeks post-autograft with overall remissions of 42-202 weeks. The prediction of leukaemia-free survival based on these results is 58% at 3 years. The procedure was well tolerated and resulted in little morbidity and no mortality.
We compared the outcome of marrow transplantation with that of continued chemotherapy for adults with acute nonlymphoblastic leukemia who achieve a first remission. From May 1977 to July 1982, 111 consecutive adults (ages 17 to 50) with newly diagnosed acute nonlymphoblastic leukemia were treated with induction chemotherapy. Ninety patients (81%) had a complete remission. Forty-four remission patients had available donors: 33 received a transplant and 11 did not. Forty-six patients in remission without matched donors were treated with continued chemotherapy. Kaplan-Meier estimates of 5-year, disease-free survival from complete remission are 49% +/- 18% for the transplant group and 20% +/- 13% for the chemotherapy group. When compared to the chemotherapy group, patients undergoing transplantation had a higher risk of dying during the first 6 months after remission induction but a lower risk of dying thereafter. Within the transplant group, only age influenced survival. Within the chemotherapy group, a leukocyte count of greater than 10 000 mm3 at diagnosis, a French-American-British (FAB) Cooperative Group morphologic status of M-4, M-5, or M-6, and the presence of infection at diagnosis were all associated with shorter survival.
We identified 18 patients with an inversion of chromosome 16, inv(16)(p13q22), among 308 patients with newly diagnosed acute nonlymphocytic leukemia. Each of these 18 patients had acute myelomonocytic leukemia (M4 subtype) and eosinophils with distinctly abnormal morphology, cytochemical staining, and ultrastructure. These eosinophils constituted from 1 to 33 per cent of the nucleated marrow cells. In our series, every patient with acute myelomonocytic leukemia and abnormal eosinophils also had an abnormal chromosome 16. This subgroup of M4 patients had a good response to intensive therapy designed to induce remission; 13 of 17 treated patients entered a complete remission, and 10 remain in first remission. Thus, patients with an inversion of chromosome 16 appear to represent a unique cytogenetic-clinicopathological subtype of acute nonlymphocytic leukemia with a favorable prognosis.
Using a methotrexate cell synchronization technique, we have successfully studied chromosome preparations of bone marrow biopsies from 49 of 51 patients with acute nonlymphocytic leukemia (ANLL). Clonal chromosomal abnormalities were detected in 46 patients, and one of eight types of recurrent chromosomal aberrations were found in 31 patients. One of these types represents a new chromosome defect [inv(16)(p13.1q22)], found in four patients with ANLL-M2, -M4. Chromosome preparations from cultured lymphocytes of two of the four patients were analyzed for the presence of chromosome fragile sites. Both cases showed a frequent break at band 16q22, an intriguing finding that suggests a possible correlation between a fragile site and predisposition to chromosomal rearrangement in human neoplasia.
Recently, several specific chromosomal abnormalities have been associated with distinctive clinical and/or morphological subtypes of acute nonlymphocytic leukemia (ANLL). To further investigate the clinical utility of karyotype analysis in ANLL, we have examined G-banded metaphase chromosomes at diagnosis in 61 consecutive patients. Of the 60 patients who had adequate mitoses, 47 (78%) had a clonal chromosome abnormality. The sole karyotypic abnormality found in 5 patients was a del(16)(q22). The unique pretreatment characteristic of these 5 patients was marrow eosinophilia ranging from 8% to 54%. No other patient had more than 4% marrow eosinophils. Among the patients with eosinophilia, all had Auer rods, serum muramidase was elevated in the 4 tested, and 4 had hepatomegaly at presentation. Both patients who survived initial treatment remain in complete remission at 23+ and 33+ mo. The data suggest that we have identified a new cytogenetic-clinical subtype of ANLL defined by the del(16)(q22).
The evidence presented provides the basis for the current notion that chromosome changes are among the critical events that lead to leukaemic tansformation. More detailed and sophisticated analysis of clinical and cytogenetic parameters will lead to the identification of further associations analogous to the t(15q+;17q-) with APL and the 14q+ with B-cell ALL. An accurate history of exposure to potential mutagens related to occupation, medical history, or other exposure, coupled with a careful record of ethnic background and evidence of a familial history of malignancy is essential if specific types of chromosome changes are to be correlated with these factors. Ultimately, the authors' goal is to understand why the chromosome changes seen in myeloid differ from those in lymphoid malignancies. As their knowledge of the human gene map increases, they will be able to relate the genes carried on the affected chromosomes to the biochemical abnormalities of the malignant cells. This will provide them with the understanding essential for both classification and improved specific therapy for patients with acute leukaemia.
The actual (not projected) 3-year survival was 59% for the first 22 patients transplanted while in remission described above. The median survival from transplantation will be ≥ 44 months, and the median time from initial diagnosis and treatment will be > 47 months. These figures are superior to any yet reported for patients treated with combination chemotherapy. The actuarial analysis of the subsequent 53 patients and the reports by two other marrow transplant teams provide additional evidence of the superiority of the marrow transplant regimens. A comparison of median survival data is informative but not definitive. The major question is how many patients are actually being cured. The apparent cure of end-stage patients with marrow transplantation, now borne out by 6-10 years of followup, indicates that many of the patients transplanted in first remission are likely to be cured. The actuarial analysis indicates that marrow transplantation for patients between 20 and 30 years of age with ANL in first remission will cure slightly more than one half of the patients. For patients <20 years old, the cure rate will be superior, and for those >30 years old, the results will be worse.