Leukemogenesis Research Articles

Semi-mechanistic population PK/PD model to aid clinical understanding of myelodysplastic syndromes following treatment with Venetoclax and Azacitidine.

Myelodysplastic syndromes (MDS) represent a group of bone marrow disorders involving cytopenias, hypercellular bone marrow, and dysplastic hematopoietic progenitors. MDS remains a challenge to treat due to the complex interplay between disease-induced and treatment-related cytopenias. Venetoclax, a selective BCL-2 inhibitor, in combination with azacitidine, a hypomethylating agent, is currently being investigated in patients with previously untreated higher-risk MDS. We present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed using preliminary clinical data from an ongoing Phase 1b study evaluating the safety and efficacy of venetoclax in combination with azacitidine in treatment-naïve patients with higher-risk MDS. Longitudinal data from 57 patients were used to develop the model, which accounted for venetoclax PK and azacitidine treatment to describe time dynamics of bone marrow blasts, neutrophils, red blood cells, and platelets. The proliferation and maturation of progenitor cells in the bone marrow to peripheral cells is described via three parallel connected transit models including feedback terms. The model also accounted for bone marrow crowding and its impact on hematopoiesis. Model validation demonstrated adequate goodness-of-fit, visual and numerical predictive checks. Model predicted complete remission (CR) rates and marrow complete remission (mCR) rates closely matched observed rates in the clinical study, and simulated efficacy (recovery of blast count, CR, and mCR rates) and safety (neutropenia and thrombocytopenia) endpoints aligned with expected outcomes from various dosing regimens. Importantly, the semi-mechanistic model may aid understanding and discriminating between disease-driven and drug-induced cytopenias.

NPM1 Mutation Detected: Does Blast Count Matter?

NPM1 Mutation Detected: Does Blast Count Matter?

Using Different Vaf Cut-Offs, Myeloid NGS Analysis of 924 Paired Peripheral Blood/Bone Marrow Samples Yielding 6944 Result Pairs Reveal Peripheral Blood As Safe Alternative Sample to Bone Marrow, Irrespective of the Degree of Neutropenia or Circulating Blast Counts

Using Different Vaf Cut-Offs, Myeloid NGS Analysis of 924 Paired Peripheral Blood/Bone Marrow Samples Yielding 6944 Result Pairs Reveal Peripheral Blood As Safe Alternative Sample to Bone Marrow, Irrespective of the Degree of Neutropenia or Circulating Blast Counts

Future directions in myelodysplastic syndromes/neoplasms and acute myeloid leukaemia classification: from blast counts to biology.

Myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukaemia (AML) are neoplastic haematopoietic cell proliferations that are diagnosed and classified based on a combination of morphological, clinical and genetic features. Specifically, the percentage of myeloblasts in the blood and bone marrow is a key feature that has historically separated MDS from AML and, together with several other morphological parameters, defines distinct disease entities within MDS. Both MDS and AML have recurrent genetic abnormalities that are increasingly influencing their definitions and subclassification. For example, in 2022, two new MDS entities were recognised based on the presence of SF3B1 mutation or bi-allelic TP53 abnormalities. Genomic information is more objective and reproducible than morphological analyses, which are subject to interobserver variability and arbitrary numeric cut-offs. Nevertheless, the integration of genomic data with traditional morphological features in myeloid neoplasm classification has proved challenging by virtue of its sheer complexity; gene expression and methylation profiling also can provide information regarding disease pathogenesis, adding to the complexity. New machine-learning technologies have the potential to effectively integrate multiple diagnostic modalities and improve on historical classification systems. Going forward, the application of machine learning and advanced statistical methods to large patient cohorts can refine future classifications by advancing unbiased and robust previously unrecognised disease subgroups. Future classifications will probably incorporate these newer technologies and higher-level analyses that emphasise genomic disease entities over traditional morphologically defined entities, thus promoting more accurate diagnosis and patient risk stratification.

Overall survival in TP53-mutated AML and MDS.

TP53 mutations in patients with AML and MDS frequently portend a poor prognosis, related to both p53 allele status and blast count. In 2022, the ICC and WHO released updated guidelines for classifying p53-mutated AML/MDS. The characteristics of p53 mutations, their associated co-mutations, and their effects on overall survival (OS) are not known in the context of these new guidelines. A retrospective chart review was undertaken for all patients with AML or MDS and at least one TP53 mutation detected on next generation sequencing (NGS) at Yale New Haven Hospital from 2015 to 2023. All patients (N = 210) met criteria for one of the 5 diagnostic classes based on WHO and ICC guidelines. Kaplan-Meier curves with associated log-rank testing and Cox proportional hazards model quantified the effects of clinical and molecular data on survival. Multi-hit pathogenic mutations were related to poorer OS in MDS but not AML using either the WHO (p = .02) or the ICC (p = .01) diagnostic criteria. The most significant predictors of OS in the sample overall were platelet count < 50K (HR: 2.01, 95% CI [1.47, 2.75], p < .001) and TP53 VAF ≤ 40% (HR: 0.68, 95% CI[0.50, 0.91], p = .01). Blast count ranges, complex karyotype, and p53 mutation type or location, showed no association with OS. In our cohort defined by the 2022 ICC and WHO criteria, VAF and thrombocytopenia, rather than blast count or p53 mutation features, significantly predicted OS. These results speak to each criteria's ability to identify cases of similarly aggressive disease biology and prognosis.

White Blood Cell and Peripheral Blast Counts in Leukemia Patients with Non-Graying WBC-Diff Scattergram

Graying scattergram of White Blood Cell differential (WBC-diff) is often accompanied by blasts in the blood and/or leukocytosis in leukemia patients. Therefore, monitoring White Blood Cell (WBC) and peripheral blast count is crucial for patient management. In contrast, patients with non-graying WBC-diff scattergrams may have varying WBC counts and peripheral blasts. This study aimed to establish the cut-off values of WBC and peripheral blast counts that could predict a non-graying scattergram in leukemia patients. A retrospective descriptive study with a cross-sectional design analyzed secondary data from 21 leukemia patients. The acute and chronic leukemia diagnosis were based on bone marrow aspirates, which simultaneously showed a graying WBC-diff scattergram on Complete Blood Count (CBC). Receiver Operating Characteristic (ROC) curve analysis was conducted when the patient’s CBC displayed a non-graying scattergram. The cut-off value for WBC count was 16,380 x 109/L with an Area Under Curve (AUC) of 0.932, a sensitivity of 85.7%, p = 0.001, and the cut-off for peripheral blast count was 35.5% with an AUC of 0.872, the sensitivity of 76.2%, p=0.001. The results suggest that a non-graying scattergram of the WDF channel in leukemia is more likely associated with WBC counts below 16,380 x 109/L and peripheral blast counts below 35.5%, which have excellent and good predictive value.

A case of isolated cutaneous myeloid sarcoma preceding acute myeloid leukemia and literature review

Isolated Cutaneous Myeloid Sarcoma (icMS) and Aleukemic Leukemia Cutis (ALC) are cutaneous extramedullary manifestations of leukemia in which leukemic cells infiltrate the skin before they can be identified either in the peripheral blood or in the bone marrow. We report the case of a 67-year-old patient who presented with a rapidly developing cutaneous tumour and scaly, erythematous-squamous plaques. Isolated Cutaneous Myeloid Sarcoma was diagnosed which rapidly progressed to terminal-stage Acute Myeloid Leukemia (AML). To highlight the disease characteristics of the adult-onset icMS and ALC cases that preceded AML we additionally compiled the pertinent literature of case reports of these rare conditions. We identified n=15 previously published icMS/ALC cases with adequately detailed clinical data descriptions. We could confirm the medical experience that icMS/ALC patients have an overall worse prognosis. Moreover, we could identify FAB M5 AML subtype as a significant adverse prognosticator of these patients.

AML typical mutations (CEBPA, FLT3, NPM1) identify a high-risk chronic myelomonocytic leukemia independent of CPSS molecular

AbstractMutations commonly associated with acute myeloid leukemia (AML), such as CEBPA, FLT3, IDH1/2, and NPM1, are rarely found in chronic myelomonocytic leukemia (CMML), and their prognostic significance in CMML has not been clearly identified. In 127 patients with CMML, we have retrospectively analyzed next-generation sequencing and polymerase chain reaction data from bone marrow samples collected at the time of CMML diagnosis. Seven patients harbored CEBPA mutations, 8 FLT3 mutations, 12 IDH1 mutations, 26 IDH2 mutations, and 11 NPM1 mutations. Patients with CMML harboring CEBPA, FLT3, and/or NPM1 mutations (mutCFN) more frequently had the myeloproliferative subtype, a high prevalence of severe cytopenia, and elevated blast counts. Regardless of their CMML Prognostic Scoring System molecular classification, mutCFN patients with CMML had a poor prognosis, and the multivariate analysis identified mutCFN as an independent marker of overall survival. The genetic profile of these mutCFN patients with CMML closely resembled that of patients with AML, with higher-risk clinical characteristics. Our findings lead us to suggest including the assessment of these mutations in CMML prognostic models and treating these patients with AML-type therapies, including intensive chemotherapy and allogeneic stem cell transplantation, whenever feasible. Furthermore, certain targeted therapies approved for use in AML should be considered.

A discussion of pediatric therapy-related acute myeloid leukemia with a rare t(8;16) translocation

Abstract Introduction/Objective Secondary acute myeloid leukemia is a type of blood cancer that arises after a previous myeloid neoplasm or after exposure to chemotherapy. Certain genetic mutations and chromosomal abnormalities can occur as a result of said cytotoxic drug-related effects. Here, we discuss a case of secondary acute myeloid leukemia with a rare translocation following hemophagocytic lymphohistiocytosis Etoposide treatment in a 13-year-old female. After less than a year into her initial treatment, the patient presented to the emergency department with severe bone pain. A full hematologic workup was performed, including bone marrow biopsy, flow cytometry analysis, and subsequent genetic studies. A diagnosis of therapy-related acute myeloid leukemia was made. Genetic studies revealed a rare t(8;16) translocation which presents with a unique morphology and prognosis that will be discussed here. Methods/Case Report A 13-year-old female presented to the emergency department for evaluation of fever, myalgia, and swelling in her clavicle. The patient’s history was notable for hemophagocytic lymphohistiocytosis with subsequent Etoposide chemotherapy treatment which she received less than a year prior to her visit. CBC was notable for low white blood cell count, low hemoglobin, increased neutrophilic bands, and decreased lymphocytes. Given her past medical history and worsening pain without a clear reason, hematology was consulted. Results (if a Case Study enter NA) A blast count of 61.8% was reported via flow cytometry with the cells seen in the dim CD45+, moderate to bright side-scatter region, co-expressing CD4, CD14 (dim, heterogeneous), CD15, CD16 (dim), CD64, HLA-DR, and MPO. The bone marrow biopsy was described as hypercellular with the predominant cell type as blasts at 66.4%. Numerous hemophagocytic blasts were noted as well. Acute leukemia next generation sequencing panel revealed a t(8;16)(p11;p13.3) KATA6A::CREBBP fusion without other abnormalities in the evaluated genes. This workup as a whole rendered the diagnosis of acute myeloid leukemia with KAT6A::CREBBP. Conclusion Diagnosing acute myeloid leukemia with KATA6A::CREBBP is important for prognostic factors. Knowing the patient’s history regarding her prior chemotherapy with Etoposide is also imperative for distinguishing a de novo presentation of this rare subtype, versus a therapy-related myeloid neoplasm. The patient was started on chemotherapy for her acute myeloid leukemia shortly thereafter the diagnosis.

Monitoring clonal burden as an alternative to blast count for myelodysplastic neoplasm treatment response.

Accurate assessment of therapy response in myelodysplastic neoplasm (MDS) has been challenging. Directly monitoring mutational disease burden may be useful, but is not currently included in MDS response criteria, and the correlation of mutational burden and traditional response endpoints is not completely understood. Here, we used genome-wide and targeted next-generation sequencing (NGS) to monitor clonal and subclonal molecular disease burden in 452 samples from 32 patients prospectively treated in a clinical trial. Molecular responses were compared with International Working Group (IWG) 2006-defined response assessments. We found that myeloblast percentage consistently underestimates MDS molecular disease burden and that mutational clearance patterns for marrow complete remission (mCR), which depends on myeloblast assessment, was not different than stable disease or bone marrow aplasia, underscoring a major limitation of using mCR. In contrast, achieving a complete remission (CR) was associated with the highest level of mutation clearance and lowest residual mutational burden in higher-risk MDS patients. A targeted gene panel approach was inferior to genome-wide sequencing in defining subclones and their molecular responses but may be adequate for monitoring molecular disease burden when a targeted gene is present in the founding clone. Our work supports incorporating serialNGS-based monitoring into prospective MDS clinical trials.

Chromothripsis in myeloid malignancies.

Chromothripsis refers to massive genomic rearrangements developed during a catastrophic event. In total acute myeloid leukemia (AML), the incidence of chromothripsis ranges from 0 to 6.6%, in cases of complex karyotype AML, the incidence of chromothripsis ranges from 27.3 to 100%, whereas in cases of AML with TP53 mutations, the incidence ranges from 11.1 to 90%. For other types of malignancies, the incidence of chromothripsis also varies, from 0 to 10.5% in myelodysplastic syndrome to up to 61.5% in cases of myelodysplastic syndrome with TP53 mutations.Chromothripsis is typically associated with complex karyotypes and TP53 mutations, and monosomal karyotypes are associated with the condition. ERG amplifications are frequently noted in cases of chromothripsis, whereas MYC amplifications are not. Moreover, FLT3 and NPM1 mutations are negatively associated with chromothripsis. Chromothripsis typically occurs in older patients with AML with low leukocyte counts and bone marrow blast counts. Rare cases of patients with chromothripsis who received intensive induction chemotherapy revealed low response rates and poor overall prognosis. Signal pathways in chromothripsis typically involve copy number gain and upregulation of oncogene gene sets that promote cancer growth and a concomitant copy number loss and downregulation of gene sets associated with tumor suppression functions.Patients with chromothripsis showed a trend of lower complete remission rate and worse overall survival in myeloid malignancy. Large-scale studies are required to further elucidate the causes and treatments of the condition.

A comparative retrospective study of pre-fibrotic primary myelofibrosis versus overtly fibrotic stage in Qatar: clinicopathological, genetic landscape, risk stratification and survival data (2008–2021) – a single center experience

ABSTRACT Background In MENA region, there is a lack of evidence on Primary Myelofibrosis (PMF), leading to its underrepresentation in medical literature. This study marks the first comprehensive report on PMF data in Qatar, presenting findings from a single-center study spanning 13 years (2008-2021). Methods Clinicopathological data, genetic features, and disease progression parameters of pre-PMF and overt PMF subgroups were collected. Overall survival (OS), progression-free survival (PFS), DIPSS plus four categories and merged low and high-risk DIPSS scoring groups were assessed. Results Pre-PMF patients showed higher hemoglobin (P < 0.001), and platelet counts (P < 0.05) but lower blast counts, LDH levels, constitutional symptoms (P < 0.0001), and splenomegaly (P < 0.010) than overt PMF patients. JAK2 V617F mutation was more common in pre-PMF (P = 0.059), while unfavorable karyotypes were exclusive to overt PMF (P = 0.028). Median overall survival was significantly longer at 276.9 months (IQR: 315.9, 276.9 months) to what was previously reported. Overt PMF patients predominantly fell into the higher DIPSS risk category (P < 0.001) and showed greater disease progression than pre-PMF (P < 0.0001). Complications including refractory anaemia (P < 0.001) and leukemic transformation (P = 0.043), increased notably in the high-risk group. Furthermore, 86.2% of high-risk patients required treatment versus 59.4% of the lower-risk group (P = 0.020). Conclusions To the best of our knowledge our research represents the first and largest published dataset on PMF in MENA region to be published. Merged DIPSS plus scoring came to be a pragmatic tool for defining high-risk patients who significantly differ in mortality, progression, need for treatment and leukemic transformation.

CXCR4 as a therapeutic target in acute myeloid leukemia.

Extensive research on the CXCL12-CXCR4 axis in acute myeloid leukemia (AML) has resulted in the incorporation of novel anti-leukemia drugs targeting this axis into therapeutic strategies. However, despite this progress, a comprehensive and up-to-date review addressing the role of the CXCL12-CXCR4 axis in AML's oncogenic processes is lacking. In this review, we examine its molecular aspects influencing cancer progression, such as its impact on autonomous proliferation, apoptotic regulation, chemoresistance mechanisms, and interactions with non-leukemic cells such as MSCs and Treg cells. Additionally, we explore clinical implications, including prognosis, correlation with WBC count, blast count in the bone marrow and peripheral blood, as well as its association with FLT3-ITD, NPM1 mutations, and FAB classification. Finally, this paper extensively discusses drugs that specifically target the CXCL12-CXCR4 axis, including plerixafor/AMD3100, ulocuplumab, peptide E5, and motixafortide, shedding light on their potential therapeutic value in the treatment of AML.

The prognostic effect of blast count in TP53 mutant myeloid neoplasms –the Minnesota experience

In 2022, the World Health Organization (WHO) and International Consensus Classification (ICC) recognized TP53 as an entity-defining alteration in myeloid neoplasms, yet with differing criteria that could lead to discrepant diagnoses and affect clinical trial eligibility. We studied 67 patients with TP53 mutant myeloid neoplasms, reclassifying them using both criteria. While most cases fulfill the criteria for TP53 mutant defined entities, most discrepancies were found in cases with ≥20% blasts. Patients were stratified into three groups based on blast count (<10%, 10–19%, and ≥20%) which revealed comparable clinicopathologic features, genetic characteristics, and outcomes. Notably, patients with ≥10% blasts had shorter overall survival compared to those with <10% blasts (8.1 vs. 12.4 months; p = 0.03). This study is among the few to examine TP53 mutant myeloid neoplasms as a single entity and suggests that the 10% blast count threshold could serve as a gateway to a more harmonized classification for these patients.

Incorporation mutational profile might reduce the importance of blast count in prognostication of low-risk myelodysplastic syndromes.

Addition of molecular data to prognostic models has improved risk stratification of myelodysplastic neoplasms (MDS). However, the role of molecular lesions, particularly in the group of low-risk disease (LR-MDS), is uncertain. We evaluated a set of 227 patients with LR-MDS. Overall survival (OS) and probability of leukaemic progression were the main endpoints. RUNX1 was associated with lower OS and SF3B1 with a reduced risk of death (HR: 1.7, 95% CI, 1.1-2.9; p = 0.05; and HR: 0.23, 95% CI 0.1-0.5; p < 0.001; respectively). TP53 and RUNX1 mutations were predictive covariates for the probability of leukaemic progression (p < 0.001). Blast percentage, neither analysed as categorical (<5% vs. 5%-9%; HR: 1.3, 95% CI, 0.7-2.9; p = 0.2) nor as a continuous variable (HR: 1.07, 95% CI, 0.9-1.1; p = 0.07), had impact on survival or probability of progression (sHR: 1.05, 95% CI, 0.9-1.1; p = 0.2). These results retained statistical significance when analysis was restricted to the definition of LR-MDS according to the WHO 2022 and ICC classifications (<5% blasts). Thus, with the incorporation of molecular data, blast percentage happens to lose clinical significance both for survival and probability of progression in the group of patients with LR-MDS.

Molecular characteristics of NPM1 mutations in AML patients using targeted NGS

ABSTRACT Background Acute myeloid leukemia (AML) is a clonal hematopoietic stem cell malignancy characterized by the accumulation of myeloid progenitor cells with arrested differentiation, leading to the suppression of normal hematopoiesis. The disease exhibits significant heterogeneity, with less than 30% five-year overall survival. Nucleophosmin 1 (NPM1) is the most commonly mutated gene in adult AML, found in approximately 25–35% of patients, and is recognized as a distinct subtype by the WHO. Methods The mutational status of NPM1 was assessed using the Oncomine Myeloid research panel on the Ion5S NGS platform (Thermo Fisher Scientific, USA). Results In our AML cohort, NPM1 was the most frequently mutated gene (75%). Indel mutations in the NPM1 gene, frequently resulting in frameshift consequences, show a statistically significant difference in variant allele frequency (VAF) compared to other mutation types. Specifically, NPM1-mutated cases exhibit a VAF that is positively correlated with initial bone marrow (BM) blast counts. Univariate logistic regression analysis reveals that a high VAF is significantly associated with non-complete remission (Non-CR), while a low VAF is significantly associated with complete remission (CR), indicating a statistically significant difference in outcomes (p = 0.012). Conclusion Targeted NGS technology enables the simultaneous analysis of multiple AML-relevant genes, offering a comprehensive mutational profile that supports risk stratification, diagnosis, and personalized treatment. Our findings highlight the significant impact of NPM1 mutations on patient outcomes, revealing their molecular characteristics and their correlation with different clinical parameters.

NPM1-Mutated Myeloid Neoplasms Irrespective of Blast Count Are Associated With Better Outcomes With Acute Myeloid Leukemia Treatment Approach

NPM1-Mutated Myeloid Neoplasms Irrespective of Blast Count Are Associated With Better Outcomes With Acute Myeloid Leukemia Treatment Approach

MDS-570 NPM1-Mutated Myeloid Neoplasms Irrespective of Blast Count Are Associated With Better Outcomes With Acute Myeloid Leukemia Treatment Approach

MDS-570 NPM1-Mutated Myeloid Neoplasms Irrespective of Blast Count Are Associated With Better Outcomes With Acute Myeloid Leukemia Treatment Approach

Comparative Analysis of AML Classification Systems: Evaluating the WHO, ICC, and ELN Frameworks and Their Distinctions.

Comprehensive analyses of the molecular heterogeneity of acute myelogenous leukemia, AML, particularly when malignant cells retain normal karyotype, has significantly evolved. In 2022, significant revisions were introduced in the World Health Organization (WHO) classification and the European LeukemiaNet (ELN) 2022 guidelines of acute myeloid leukemia (AML). These revisions coincided with the inception of the first version of the International Consensus Classification (ICC) for AML. These modifications aim to improve diagnosis and treatment outcomes via a comprehensive incorporation of sophisticated genetic and clinical parameters as well as facilitate accruals to innovative clinical trials. Key updates include modifications to the blast count criteria for AML diagnosis, with WHO 2022 eliminating the ≥20% blast requirement in the presence of AML-defining abnormalities and ICC 2022 setting a 10% cutoff for recurrent genetic abnormalities. Additionally, new categories, such as AML with mutated TP53 and MDS/AML, were introduced. ELN 2022 guidelines retained risk stratification approach and emphasized the critical role of measurable residual disease (MRD) that increased the use of next-generation sequencing (NGS) and flow cytometry testing. These revisions underscore the importance of precise classification for targeted treatment strategies and improved patient outcomes. How much difference versus concordance these classifications present and the impact of those on clinical practice is a continuing discussion.

Human Leukocyte Antigen-DR and Cluster Designation 34: Double-negative Acute Myeloid Leukemias – Our Experience in Clinical Setting

Abstract Introduction: Dual negativity for cluster designation (CD) 34 and human leukocyte antigen (HLA)-DR antigen in leukemia panel is an important finding in clinical practice. The combination of this finding though seen classically in acute promyelocytic leukemia (APL) is not specific to it but can be seen in many other myeloid leukemias like the ones associated with nucleophosmin 1 (NPM1) or FMS-related tyrosine kinase 3 gene-internal tandem duplication (FLT3-ITD) abnormalities. It is important to identify APL from non-APL leukemia as treatment and prognosis vary. Aims and Objectives: We analyzed CD 34 and HLA-DR dual-negative acute myeloid leukemia (AML) cases presented to us over 2.5 years (26 cases) and segregated them into APL and non-APL groups to study their morphological/flow cytometric and cytogenetic profile and correlation with treatment response. Materials and Methods: It was a prospective study including all newly diagnosed AMLs showing CD 34 and HLA-DR dual negativity in flow cytometry profile. Cases in which complete information/cytogenetics/molecular profile were not available, were excluded from the study. The patients were followed up till the end of induction to look for morphological response to induction therapy. The clinical and treatment records were pulled out from the patient database after ethical committee clearance. Results: A total of 139 new AML cases were encountered during the study period out of which 28 (20%) were found to be dual negative for CD34 and HLA-DR. The non-APL group showed higher mean age, TLC at baseline, variable morphology, and more number of aberrant expression on flow cytometry profile. No significant difference was noted in terms of gender, presence of hepatosplenomegaly, DIC as complication, or percentage of blasts/blasts equivalent at baseline. Our study found that while all APL patients had PML-RARA, the associated molecular abnormalities were much lesser as compared to the non-APL group which showed a variety of abnormalities such as NPM1, FLT3, RAS mutation, and mutations involving epigenetic modifiers. The response rate to induction therapy was significantly lower in the non-APL group as compared to the APL group. Conclusion: The non-APL myeloid leukemia which is dual negative is commonly found to be associated with cup-shaped morphology, NPM, or FLT3-ITD mutation along with other abnormalities. These patients were older in age, showed higher TLC and higher blast counts, associated with poorer response to induction therapy as compared to the APL group.