Prophylactic therapy using epigenetic agents for RUNX1::RUNXT1-positive high-risk AML after Allo-HSCT.

Disease recurrence is the leading cause of treatment failure in patients with RUNX1::RUNXT1-positive acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Post-transplant maintenance therapy, guided by monitoring minimal residual disease (MRD), is commonly administered; however, relapse rates remain high. This prospective study aimed to assess the effectiveness and safety of epigenetic agents as prophylactic therapy in patients with RUNX1::RUNXT1-positive AML. Thirty high-risk patients received prophylactic therapy (n = 17 and n = 13 in the chidamide and AZA groups, respectively) between January 2019 and July 2023. 34 high-risk patients who received preemptive treatment due to molecular relapse were included in the analysis. The two-year relapse-free survival (RFS) and overall survival (OS) were significantly higher in the prophylactic group compared to the preemptive group (82.82% vs. 51.38%, P = 0.014; 86.42% vs. 56.16%, P = 0.025, respectively); 2-year cumulative incidence of relapse rates were 13.8% and 36.40%, respectively (P = 0.037). In conclusion, prophylactic therapy with epigenetic agents may improve long-term prognosis and is well-tolerated in patients with RUNX1::RUNXT1-positive high-risk AML. Timely post-transplant prophylactic therapy may be more effective than preemptive therapy based on positive MRD results.

RUNX1::RUNX1T1 Acute Myeloid Leukemia Cytogenetically Showing t(6;8)(p23;q22).

Runt-related transcription factor 1 (RUNX1)::RUNX1 partner transcriptional co-repressor 1 (RUNX1T1) acute myeloid leukemia (AML) is a subtype of acute leukemia primarily classified as French American British M2. RUNX1::RUNX1T1 transcript is formed by a reciprocal translocation between chromosomes 8q22 and 21q22. However, we encountered a case of AML that showed molecular positivity for RUNX1::RUNX1T1 fusion transcript but exhibited cytogenetically atypical translocation t(6;8). Fluorescence in situ hybridization (FISH) analysis, in combination with G-banding, clarified the three-way translocation t(6;21;8)(p25;q22;q22), which was partially cryptic. The case emphasizes the importance of employing molecular analysis alongside cytogenetics to determine disease subtypes in patients with acute leukemia.

t(2;2;21;8)(p21;q37;q22;q22), a novel four-way complex translocation involving variant t(8;21) in case of acute myeloid leukemia : A case report and literature review.

Chromosomal translocation serves as a crucial diagnostic marker in the classification of acute myeloid leukemia. Among the most prevalent cytogenetic abnormalities is t(8;21)(q22;q22), typically associated with the FAB subtype AML-M2. On occasion, alternative forms of t(8;21) have been observed. This report presents a case of AML with RUNX1::RUNX1T1, wherein the karyotype revealed t(2;2;21;8)(p21;q37;q22;q22), representing the first instance of a variant t(8;21) involving both chromosomes 2. The combination of routine karyotype analysis and fluorescence in situ hybridization proves to be an effective method for identifying complex translocations of t(8;21).

Combination of eriocalyxin B and homoharringtonine exerts synergistic anti-tumor effects against t(8;21) AML.

Understanding the molecular pathogenesis of acute myeloid leukemia (AML) with well-defined genomic abnormalities has facilitated the development of targeted therapeutics. Patients with t(8;21) AML frequently harbor a fusion gene RUNX1-RUNX1T1 and KIT mutations as "secondary hit", making the disease one of the ideal models for exploring targeted treatment options in AML. In this study we investigated the combination therapy of agents targeting RUNX1-RUNX1T1 and KIT in the treatment of t(8;21) AML with KIT mutations. We showed that the combination of eriocalyxin B (EriB) and homoharringtonine (HHT) exerted synergistic therapeutic effects by dual inhibition of RUNX1-RUNX1T1 and KIT proteins in Kasumi-1 and SKNO-1 cells in vitro. In Kasumi-1 cells, the combination of EriB and HHT could perturb the RUNX1-RUNX1T1-responsible transcriptional network by destabilizing RUNX1-RUNX1T1 transcription factor complex (AETFC), forcing RUNX1-RUNX1T1 leaving from the chromatin, triggering cell cycle arrest and apoptosis. Meanwhile, EriB combined with HHT activated JNK signaling, resulting in the eventual degradation of RUNX1-RUNX1T1 by caspase-3. In addition, HHT and EriB inhibited NF-κB pathway through blocking p65 nuclear translocation in two different manners, to synergistically interfere with the transcription of KIT. In mice co-expressing RUNX1-RUNX1T1 and KITN822K, co-administration of EriB and HHT significantly prolonged survival of the mice by targeting CD34+CD38- leukemic cells. The synergistic effects of the two drugs were also observed in bone marrow mononuclear cells (BMMCs) of t(8;21) AML patients. Collectively, this study reveals the synergistic mechanism of the combination regimen of EriB and HHT in t(8;21) AML, providing new insight into optimizing targeted treatment of AML.

Single-cell RNA-seq reveals novel immune-associated biomarkers for predicting prognosis in AML patients with RUNX1::RUNX1T1.

Acute myeloid leukemia (AML) with t(8;21)(q22;q22);(RUNX1::RUNX1T1) is highly heterogeneous and malignant. It has a relapse rate of nearly 40 %, resulting in clinical resistance or refractoriness to chemotherapy. Immune cells, particularly CD4(+) T and CD8(+) T lymphocytes, have been discovered to be dysfunctional in this condition, and functional recovery shows promising efficiency in preclinical trials. Here, with single-cell transcriptomic data from de novo AML patients with RUNX1::RUNX1T1 and at various stages following disease progression, we investigated the genes correlated with T-cell proliferation and activation. In leukemia cells, ADA, AHCY, GPN3 and LTBR were markedly highly expressed compared to those in T-cell at diagnosis, and they tended to increase with disease progression. Additionally, we discovered that AHCY was an effective biomarker to predict the overall survival as well as relapse-free survival of AML patients with RUNX1::RUNX1T1. The correlation of AHCY with infiltrated immune cells and immune checkpoints was also investigated. AML cohorts from two other independent studies, TCGA LAML (n = 145) and the GEO dataset (n = 104), also demonstrated an inferior outcome for AML patients with high AHCY expression. In conclusion, our research revealed that AHCY might function as a novel indicator to predict the prognosis and efficiency of T-cell proliferation and activation in AML patients with RUNX1::RUNX1T1.

Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia.

MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in MGA have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with RUNX1::RUNX1T1, however, very little is known about the impact of these MGA alterations on normal hematopoiesis or disease progression. We show that representative MGA mutations identified in patient samples abolish protein-protein interactions and transcriptional activity. Using a series of human and mouse model systems, including a newly developed conditional knock-out mouse strain, we demonstrate that loss of MGA results in upregulation of MYC and E2F targets, cell cycle genes, mTOR signaling, and oxidative phosphorylation in normal hematopoietic cells, leading to enhanced proliferation. The loss of MGA induces an open chromatin state at promotors of genes involved in cell cycle and proliferation. RUNX1::RUNX1T1 expression in Mga-deficient murine hematopoietic cells leads to a more aggressive AML with a significantly shortened latency. These data show that MGA regulates multiple pro-proliferative pathways in hematopoietic cells and cooperates with the RUNX1::RUNX1 T1 fusion oncoprotein to enhance leukemogenesis.

Systemic Mastocytosis with Associated Hematological Neoplasms. Diagnostic features and unique response pattern to tyrosine kinase inhibitors and allo-bone marrow transplantation therapy / Mastocitosis sistémica con neoplasias hematológicas asociadas. Características diagnósticas y patrón de respuesta único a los inhibidores de la tirosina cinasa y al tratamiento de trasplante de médula ósea

Systemic Mastocytosis is a clonal proliferation of mast cells; in a significant fraction of cases it is associated with another concurrent hematological neoplasm. Molecular analysis of KIT mutations and other associated genetic alterations suggest a common origin in the stem cell compartment. Mast cell infiltration patterns in bone marrow biopsy may be subtle in cases associated with t (8;21) AML. Here we report three cases of clonally related SM-AHN, two cases with SM-CMML and one case with SM- t (8;21) AML. We describe in detail the bone marrow infiltration pattern at diagnosis and during the course of treatment with allogeneic stem cell transplant and novel TK inhibitors, showing the unique dynamics of mast cell clearance after therapy.(AU)

La mastocitosis sistémica es una proliferación clonal de mastocitos que puede asociarse con otra neoplasia hematológica concurrente en una fracción significativa de los casos. El análisis molecular de mutaciones de KIT y otras alteraciones genéticas asociadas indican un origen común en el compartimento de células madre. Los patrones de infiltración de mastocitos en la biopsia de médula ósea pueden ser sutiles en los casos asociados con AML t (8; 21). Aquí se describen 3 casos de MS-NHA, 2 casos con MS-LMMC y un caso con MS-t (8; 21) LMA. Describimos en detalle el patrón de infiltración de la médula ósea en el momento del diagnóstico y durante el curso del tratamiento con alotrasplante de células madre y nuevos inhibidores de TK, mostrando la dinámica de la depuración de mastocitos después de la terapia.(AU)

Systemic Mastocytosis with Associated Hematological Neoplasms. Diagnostic features and unique response pattern to tyrosine kinase inhibitors and allo-bone marrow transplantation therapy.

Systemic Mastocytosis is a clonal proliferation of mast cells; in a significant fraction of cases it is associated with another concurrent hematological neoplasm. Molecular analysis of KIT mutations and other associated genetic alterations suggest a common origin in the stem cell compartment. Mast cell infiltration patterns in bone marrow biopsy may be subtle in cases associated with t (8;21) AML. Here we report three cases of clonally related SM-AHN, two cases with SM-CMML and one case with SM- t (8;21) AML. We describe in detail the bone marrow infiltration pattern at diagnosis and during the course of treatment with allogeneic stem cell transplant and novel TK inhibitors, showing the unique dynamics of mast cell clearance after therapy.

Application of prophylactic or pre-emptive therapy after allogeneic transplantation for high-risk patients with t(8;21) acute myeloid leukemia.

OBJECTIVES: To determine the impact of pretransplant measurable residual disease (pre-MRD) and the efficacy of maintenance therapy in t(8;21) acute myeloid leukemia (AML) patients after allogeneic hematopoietic cell transplantation (allo-HCT). METHODS: We retrospectively analyzed 100 t(8;21) AML patients who underwent allo-HCT between 2013 and 2022. 40 patients received pre-emptive therapy including immunosuppressant adjustment, azacitidine, and donor lymphocyte infusion (DLI) combined with chemotherapy. 23 patients received prophylactic therapy, including azacitidine or chidamide. RESULTS: Patients with a positive pre-MRD (pre-MRDpos) had a higher 3-year cumulative incidence of relapse (CIR) (25.90% [95% CI, 13.87%-39.70%] vs 5.00% [95% CI, 0.88%-15.01%]; P = 0.008). Pre-MRDpos patients were less likely to have a superior 3-year disease-free survival (DFS) (40.83% [95% CI, 20.80%-80.16%]) if their MRD was still positive at 28 days after transplantation (post-MRD28pos). The 3-year DFS and CIR were 53.17% (95% CI, 38.31% - 73.80%) and 34.87% (95% CI, 18.84% - 51.44%), respectively, for patients receiving pre-emptive interventions after molecular relapse. The 3-year DFS and CIR were 90.00% (95%CI, 77.77% - 100%) and 5.00% (95%CI, 0.31% - 21.10%), respectively, for high-risk patients receiving prophylactic therapy. In most patients, epigenetic-drug-induced adverse events were reversible with dose adjustment or temporary discontinuation. CONCLUSION: Patients with pre-MRDpos and post-MRD28pos were more likely to have higher rates of relapse and inferior DFS, even after receiving pre-emptive interventions. Prophylactic therapy may be a better option for high-risk t(8;21) AML patients; however, this warrants further investigation.

Deregulated Gene Expression Profiles and Regulatory Networks in Adult and Pediatric RUNX1/RUNX1T1-Positive AML Patients.

Acute myeloid leukemia (AML) is a heterogeneous and complex disease concerning molecular aberrations and prognosis. RUNX1/RUNX1T1 is a fusion oncogene that results from the chromosomal translocation t(8;21) and plays a crucial role in AML. However, its impact on the transcriptomic profile of different age groups of AML patients is not completely understood. Here, we investigated the deregulated gene expression (DEG) profiles in adult and pediatric RUNX1/RUNX1T1-positive AML patients, and compared their functions and regulatory networks. We retrospectively analyzed gene expression data from two independent Gene Expression Omnibus (GEO) datasets (GSE37642 and GSE75461) and computed their differentially expressed genes and upstream regulators, using limma, GEO2Enrichr, and X2K. For validation purposes, we used the TCGA-LAML (adult) and TARGET-AML (pediatric) patient cohorts. We also analyzed the protein-protein interaction (PPI) networks, as well as those composed of transcription factors (TF), intermediate proteins, and kinases foreseen to regulate the top deregulated genes in each group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses were further performed for the DEGs in each dataset. We found that the top upregulated genes in (both adult and pediatric) RUNX1/RUNX1T1-positive AML patients are enriched in extracellular matrix organization, the cell projection membrane, filopodium membrane, and supramolecular fiber. Our data corroborate that RUNX1/RUNX1T1 reprograms a large transcriptional network to establish and maintain leukemia via intricate PPI interactions and kinase-driven phosphorylation events.

Fusion Gene-Based Classification of Variant Cytogenetic Rearrangements in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) represents a heterogeneous disease entity that is continuously moving to a more genetically defined classification. The classification of AML with recurrent chromosomal translocations, including those involving core binding factor subunits, plays a critical role in diagnosis, prognosis, treatment stratification, and residual disease evaluation. Accurate classification of variant cytogenetic rearrangements in AML contributes to effective clinical management. We report here the identification of four variant t(8;V;21) translocations in newly diagnosed AML patients. Two patients showed a t(8;14) and a t(8;10) variation, respectively, with a morphologically normal-appearing chromosome 21 in each initial karyotype. Subsequent fluorescence in situ hybridization (FISH) on metaphase cells revealed cryptic three-way translocations t(8;14;21) and t(8;10;21). Each resulted in RUNX1::RUNX1T1 fusion. The other two patients showed karyotypically visible three-way translocations t(8;16;21) and t(8;20;21), respectively. Each resulted in RUNX1::RUNX1T1 fusion. Our findings demonstrate the importance of recognizing variant forms of t(8;21) translocations and emphasize the value of applying RUNX1::RUNX1T1 FISH for the detection of cryptic and complex rearrangements when abnormalities involving chromosome band 8q22 are observed in patients with AML.

Risk factors for post-transplant relapse and survival in younger adult patients with t(8;21)(q22;q22) acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation: A multicenter retrospective study.

Background: Outcomes of patients with t(8;21)(q22;q22) acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain heterogeneous. Methods: To identify the risk factors for relapse and survival after allo-HSCT in t(8;21) AML patients, we retrospectively evaluated the clinical and prognostic information of 142 patients with t(8;21) AML undergoing allo-HSCT between January 2002 and September 2018 at 15 hematology research centers in China. Results: Twenty-nine patients (20%) relapsed after undergoing allo-HSCT. A > 1-log reduction in RUNX1/RUNX1T1-based minimal residual disease (MRD) directly before allo-HSCT and a > 3-log reduction within the first 3 months after allo-HSCT were associated with a significantly lower post-transplant 3-year cumulative incidence of relapse (CIR, 9% vs. 62% and 10% vs. 47%,all P < 0.001), whereas transplantation during the second complete remission (CR2, 39% vs. 17% during CR1, P = 0.022), during relapse (62% vs. 17% during CR1, P < 0.001) and KIT D816 mutations at diagnosis (49% vs. 18%, P = 0.039) were related to a significantly higher 3-year CIR. Multivariate analysis demonstrated that a > 1-log reduction in MRD directly before transplantation (CIR: hazard ratio(HR), 0.21 [0.03-0.71], P = 0.029; overall survival (OS): HR = 0.27 [0.08-0.93], P = 0.038) and a > 3-log reduction in post-transplant MRD within the first 3 months (CIR: HR = 0.25 [0.07-0.89], P = 0.019; OS: HR = 0.38 [0.15-0.96], P = 0.040) were independent favorable prognostic factors, and transplantation during relapse (CIR: HR = 5.55 [1.23-11.56], P = 0.041; OS: HR = 4.07 [1.82-20.12], P = 0.045) were independent adverse prognostic factors for post-transplant relapse and survival in patients with t(8;21) AML. Conclusion: Our study suggests that for patients with t(8;21) AML undergoing allo-HSCT, it would be better to receive transplantation during CR1 with a MRD directly before transplantation achieving at least 1-log reduction. MRD monitoring in the first 3 months after allo-HSCT might be robust in predicting relapse and adverse survival after allo-HSCT.

Acute myeloid leukemia patients with variant or unusual translocations involving chromosomes 8 and 21 - A comprehensive cytogenetic profiling of three cases with review of literature.

Background: t(8;21)(q22;q22) is the most frequent recurrent translocation in acute myeloid leukemia (AML) resulting in an in-frame fusion of RUNX1/RUNX1T1 that regulates various genes involved in the signaling pathways. This leukemogenic alteration is usually associated with a favorable clinical outcome. Variants of t(8;21) can be formed involving a third or fourth chromosome in ~3-4% of t(8;21)-AML. Due to the rarity of variant t(8;21), its clinicopathological features and prognostic significance are still unclear. Here we present three AML cases with cryptic rearrangements of chromosomes 8 and 21 without standard RUNX1/RUNX1T1. Materials and Methods: Conventional karyotyping and fluorescence in situ hybridization and/or spectral karyotyping of the pretreatment bone marrow aspirate of de novo AML patients were performed to delineate chromosomal abnormalities. Results: We identified three cases with novel variants of t(8;21); der(13)t(8;21;13), isodicentric derivative 8 with chromosome 21[,+idicder(8)(q11.1)t(8;21)(q22;q11.1)] and der(21)t(8;12;21)(q22;q?;q22). Conclusion: AML with t(8;21)(q22;q22);RUNX1-RUNX1T1 forms a distinct WHO subcategory and hence the identification of variants or unusual translocations associated with t(8;21) deserves more attention. Contribution to the variant/ unusual t(8;21) database will further refine the risk stratification and may help to significantly advance the current treatment regimen.

Immunohistochemical Staining to Identify Concomitant Systemic Mastocytosis in Acute Myeloid Leukemia with RUNX1::RUNX1T1.

Systemic mastocytosis with associated hematological neoplasm (SM-AHN) poses diagnostic challenges because of the coexistence of atypical mast cell proliferation and hematological neoplasms. We assessed the presence of SM-AHN in patients with acute myeloid leukemia (AML) with RUNX1::RUNX1T1 from 2014 to 2020. Bone marrow (BM) samples were evaluated for mast cell aggregates using CD117 and CD25 immunohistochemical (IHC) staining. The KIT D816V variant burden at diagnosis and post induction was assessed using droplet digital PCR. Among 23 patients diagnosed as having AML with RUNX1::RUNX1T1, four (17.4%) were also diagnosed as having SM-AHN. No significant differences in clinical characteristics or overall survival (P=0.565) were observed between patients with or without SM-AHN, except for the presence of KIT variants (P=0.040). After induction therapy, IHC staining revealed the presence of mast cell aggregates in the BM, and the KIT D816V variant burden decreased with decreasing blast count and was similar in BM aspirates, smear slides, and sections. Concomitant SM-AHN was not infrequent in AML patients with RUNX1::RUNX1T1. This study showed the importance of CD117 and CD25 IHC staining after induction chemotherapy for SM-AHN screening, especially in patients with KIT variants.

Mutated KIT Tyrosine Kinase as a Novel Molecular Target in Acute Myeloid Leukemia.

KIT is a type-III receptor tyrosine kinase that contributes to cell signaling in various cells. Since KIT is activated by overexpression or mutation and plays an important role in the development of some cancers, such as gastrointestinal stromal tumors and mast cell disease, molecular therapies targeting KIT mutations are being developed. In acute myeloid leukemia (AML), genome profiling via next-generation sequencing has shown that several genes that are mutated in patients with AML impact patients' prognosis. Moreover, it was suggested that precision-medicine-based treatment using genomic data will improve treatment outcomes for AML patients. This paper presents (1) previous studies regarding the role of KIT mutations in AML, (2) the data in AML with KIT mutations from the HM-SCREEN-Japan-01 study, a genome profiling study for patients newly diagnosed with AML who are unsuitable for the standard first-line treatment (unfit) or have relapsed/refractory AML, and (3) new therapies targeting KIT mutations, such as tyrosine kinase inhibitors and heat shock protein 90 inhibitors. In this era when genome profiling via next-generation sequencing is becoming more common, KIT mutations are attractive novel molecular targets in AML.

[A favorable clinical course of acute myeloid leukemia with t (6;21;8)(p23;q22;q22)].

Variants of the t (8;21) (q22;q22) involving chromosome 8, 21, and other chromosomes account for about 3% of all t (8;21) (q22;q22) in patients with acute myeloid leukemia (AML). However, the prognosis of AML with variant t (8;21) remains unknown due to the scarcity of reported cases. Herein we report a case of AML with t (6;21;8) (p23;q22;q22). Fluorescence in situ hybridization confirmed a RUNX1-RUNX1T1 fusion signal on the derivative chromosome 8. This is the first report on a variant of t (8;21) involving the breakpoint 6p23. After induction chemotherapy, our patient achieved complete remission and has been stable for four years.

Case Report: Preemptive Treatment With Low-Dose PD-1 Blockade and Azacitidine for Molecular Relapsed Acute Myeloid Leukemia With RUNX1-RUNX1T1 After Allogeneic Hematopoietic Stem Cell Transplantation.

Acute myeloid leukemia (AML) patients who develop hematological relapse (HR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) generally have dismal clinical outcomes. Measurable residual disease (MRD)-directed preemptive interventions are effective approaches to prevent disease progression and improve prognosis for molecular relapsed patients with warning signs of impending HR. In this situation, boosting the graft-vs-leukemia (GVL) effect with immune checkpoint inhibitors (ICIs) might be a promising prevention strategy, despite the potential for causing severe graft-vs-host disease (GVHD). In the present study, we reported for the first time an AML patient with RUNX1-RUNX1T1 who underwent preemptive treatment with the combined application of tislelizumab (an anti-PD-1 antibody) and azacitidine to avoid HR following allo-HSCT. On day +81, molecular relapse with MRD depicted by RUNX1-RUN1T1-positivity as well as mixed donor chimerism occurred in the patient. On day +95, with no signs of GVHD and an excellent eastern cooperative oncology group performance status (ECOG PS), the patient thus was administered with 100 mg of tislelizumab on day 1 and 100 mg of azacitidine on days 1-7. After the combination therapy, complete remission was successfully achieved with significant improvement in hematologic response, and the MRD marker RUNX1-RUNX1T1 turned negative, along with a complete donor chimerism in bone marrow. Meanwhile, the patient experienced moderate GVHD and immune-related adverse events (irAEs), successively involving the lung, liver, lower digestive tract and urinary system, which were well controlled by immunosuppressive therapies. As far as we know, this case is the first one to report the use of tislelizumab in combination with azacitidine to prevent post-transplant relapse in AML. In summary, the application of ICIs in MRD positive patients might be an attractive strategy for immune modulation in the future to reduce the incidence of HR in the post-transplant setting, but safer clinical application schedules need to be explored.

Non-age-related neoplastic loss of sex chromosome correlated with prolonged survival in real-world CBF-AML patients.

In this real-world clinical study, in which we determined eligibility for allogenic hematopoietic stem cell transplantation by prognostic factors and minimal residual disease status, we retrospectively evaluated cytogenetic, genetic, and clinical features in 96 patients with core-binding factor acute myeloid leukemia (CBF-AML) including 62 patients with RUNX1/RUNX1T1 and 34 patients with CBFß/MYH11. Multivariate analyses for 5-year overall survival (OS) in CBF-AML patients revealed that age of 50 years or older (HR: 3.46, 95% CI 1.47-8.11, P = 0.004) and receiving 2 or more induction cycles (HR: 3.55, 95% CI 1.57-8.05, P = 0.002) were independently associated with worse OS and that loss of sex chromosome (LOS) was independently associated with better OS (HR: 0.09, 95% CI 0.01-0.71, P = 0.022). At the time of complete remission, all 21 karyotyped patients with LOS had a normal karyotype. Furthermore, in all 9 patients with LOS who had a mosaic of metaphase cells with and without t(8;21) or inv(16), the metaphase cells without t(8;21)/inv(16) showed a normal karyotype. These results proved that LOS was not age-related and physiological, but rather a neoplastic chromosomal abnormality.