Hematological malignancies. Acute Leukemias.

1. Dr. Samatbek Turdaliev  

2. Charalil Ashehad Anifer

Ahala Muhammad

(1. Teacher, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic

2. Students, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.)

Abstract 

Background: Acute leukemias are medical emergencies whose outcome depends on the speed and accuracy of initial differential diagnosis, yet their presenting features overlap with numerous benign and malignant conditions. Updated epidemiological data are required to inform clinical vigilance and health-service planning. 

Methods: A structured literature review (PubMed, Embase, Cochrane 1990-September 2024) was supplemented by Global Burden of Disease 2021 registry analytics. Studies reporting incidence, mortality, disability-adjusted life-years (DALYs), and diagnostic performance of morphological, immunophenotypic, or molecular tools were included; qualitative synthesis was undertaken.

Results: Between 1990 and 2021 incident AML cases rose 82 % to 144,650 globally, while deaths increased 74 % to 130-190; age-standardised incidence remained stable at 1.73/100,000, but case-fatality exceeds 85 % in adults > 50 years. ALL incidence is bimodal (1.6/100,000) with five-year survival 93 % in children yet only 34 % in adults. Low- and middle-income regions exhibit the fastest growth in both incidence and mortality. Peripheral-blood blast identification combined with a 10-colour flow panel achieves 98 % sensitivity and 94 % specificity for acute leukemia within three hours, but median diagnostic delay in resource-limited settings remains six weeks. Key differential considerations include severe infection, megaloblastic deficiency, aplastic anaemia, lymphoma, metastatic solid tumours, autoimmune cytopenias, drug toxicity, and clonal haematopoiesis of indeterminate potential; integration of morphology, immunophenotype, karyotype, FISH, and next-generation sequencing currently provides the most robust classification. 

Conclusions: Acute leukemias are rising in absolute burden and survival disparity. Prompt exclusion of mimics at first clinical contact—through systematic laboratory triage—offers the greatest leverage to reduce early mortality and should be embedded in global haematology networks.

Introduction

Acute leukemias hit hard and fast. They show up out of nowhere, and within days, everything can change. If you miss the early signs, vague symptoms can turn into serious blood shortages or organ failure in just a few weeks. Biologically, the process is just as sudden. One blood-forming cell goes off track after a few mutations, starts multiplying like crazy, and forgets how to grow up. These immature cells—blasts—take over the bone marrow, push out normal cells, and then flood into the bloodstream. Depending on their type, they’ll commit to either myeloid or lymphoid lineage. Over the past decade, we've learned that “acute leukemia” isn’t just a simple split between AML (acute myeloid leukemia) and ALL (acute lymphoblastic leukemia) anymore. It’s actually a whole mix of diseases, each shaped by unique genetic changes and mutation patterns, not to mention how the leftover disease behaves after treatment (MRD kinetics). We’ve made real progress in understanding the science, but that hasn’t translated into fair outcomes everywhere. Take pediatric ALL, for example. In wealthy countries, over 90% of kids survive five years, but for adults with ALL or for anyone with AML in most low- and middle-income countries, survival drops below 30%. The gap is huge, and it’s not closing nearly fast enough.

Clinicians face two big challenges here: first, telling leukaemia apart from all the other conditions that look like it when they first see a patient, and second, once they know it’s leukaemia, figuring out exactly which type fast enough to start the right treatment. That’s not easy, since the first symptoms—things like tiredness, shortness of breath, bleeding, fever, or blood count problems picked up on routine tests—aren’t unique. These could just as easily point to aplastic anaemia, megaloblastic deficiency, a viral infection, or even lymphoma. And sometimes, leukaemia throws a curveball. It can show up as a skin rash, a tumour behind the eye, or even sudden liver failure, which can send doctors looking for solid cancers or infections instead. Getting the diagnosis wrong isn’t just a technicality. If doctors waste time on antibiotics, steroids, or even surgery instead of starting chemotherapy, things can go downhill fast—tumours can grow, cells can break down dangerously, or there can be deadly bleeding.

In this article, we pull together the latest evidence on how common acute leukaemias are, how doctors diagnose them, and how to sort them from lookalike diseases. We use the Global Burden of Disease 2021 data for up-to-date numbers on deaths and illness, weave in the 2022 WHO classification changes, and show how today’s lab technology—flow cytometry, next-generation sequencing, and quantitative PCR—works alongside old-school clinical skills to zero in on the diagnosis. The discussion stays narrative, not broken up into bullet points, to capture how real haematologists actually think through tough cases.

Methods

A structured literature review was performed in September 2024 using PubMed, Embase, and the Cochrane Library. Search terms combined Medical Subject Headings (MeSH) and free-text phrases: “acute myeloid leukaemia”, “acute lymphoblastic leukaemia”, “epidemiology”, “incidence”, “mortality”, “DALY”, “differential diagnosis”, “cytopenia”, “bone marrow failure”, “WHO classification 2022”, and “measurable residual disease”. Only publications in English or with official English translations were considered. Population-based registries (SEER, EUROCARE, GBD) were prioritised for incidence and survival data; peer-reviewed journals with impact factor > 3 were selected for biological insights. Where 2021–2024 data were unavailable, extrapolation to 2023 was performed using Join-point regression of the most recent five-year trend. Grey literature (conference abstracts, regulatory filings) was excluded unless it provided the sole source of updated epidemiological statistics. The review was iterative: initial snowball sampling identified sentinel papers; their reference lists were hand-searched for additional sources. Quality appraisal followed the Newcastle-Ottawa scale for observational studies and the Cochrane Risk of Bias tool for randomised trials. No meta-analysis was attempted because of heterogeneity in outcome definitions and geography; instead, median values and inter-quartile ranges are reported descriptively. 

Results

Epidemiology: The Burden Continues to Rise

The GBD 2021 study documented 144 650 incident cases of AML worldwide, compared with 79 370 in 1990—an 82 % increase that outpaced global population growth. Age-standardised incidence remained stable at 1.73 per 100 000, implying that demographic ageing, rather than rising age-specific risk, explains the absolute surge. Mortality rose in parallel: 130 190 deaths in 2021 versus 74 920 in 1990, yielding a case-fatality ratio that has remained stubbornly above 85 % for adults > 50 years. Disability-adjusted life-years (DALYs) increased 24 % to 4.14 million, but the age-standardised DALY rate declined 22 %, reflecting modest gains in paediatric survival and earlier detection in some regions. 

Socio-demographic index (SDI) stratification reveals a stark epidemiological transition. High-SDI countries now record the highest incidence (2.88 per 100 000) but also the steepest mortality deceleration (EAPC −0.21), thanks to intensivist support, universal MRD monitoring, and widespread access to allogeneic transplant. Conversely, low-middle SDI regions exhibit the fastest growth in both incidence (EAPC +0.34) and mortality (EAPC +0.31), driven by urbanisation, benzene exposure, and limited pathology networks. Data for ALL are fragmented because the GBD aggregates it within “other leukaemias,” but national registries provide surrogate insight. SEER 2023 reports an overall ALL incidence of 1.6 per 100 000 in the United States, with a bimodal peak at 3–5 years and again after 70 years. Five-year relative survival for children improved from 73 % in 1990 to 93 % in 2020; adult survival languishes at 34 % overall, and below 20 % for those > 60 years. 

Clinical Presentation: The Chameleon Within Routine Practice

Acute leukemias announce themselves through one of three syndromic corridors: marrow failure, organ infiltration, or systemic inflammation. Marrow failure dominates in AML, where median diagnostic blast percentage is 60 % and residual haematopoiesis is often < 10 %. Patients report a 2- to 4-week history of exertional dyspnoea, easy bruising, or heavy menses; physical signs include pallor, petechiae concentrated on the lower limbs, and septic mouth ulcers. Fever > 38 °C is documented in 55 % of cases, yet only one-third have microbiologically proven infection at diagnosis, suggesting cytokine release rather than true sepsis. Median haemoglobin at presentation is 8.3 g dL⁻¹, platelet count 45 × 10⁹ L⁻¹, and neutrophils 0.9 × 10⁹ L⁻¹; extreme values—platelets < 10 × 10⁹ L⁻¹ or white cells > 100 × 10⁹ L⁻¹—predict early death within 7 days if treatment is withheld. 

ALL more frequently presents with overt tumour bulk: mediastinal mass in 15 % of T-ALL, hepatosplenomegaly in 60 %, and lymphadenopathy in 70 %. Bone pain is almost pathognomonic in children, occurring when blasts expand the intramedullary cavity; adults describe vague lumbar ache that is often misattributed to degenerative disease. Central nervous system (CNS) involvement—headache, diplopia, or cranial nerve palsies—occurs in 5–7 % of B-ALL and 10 % of T-ALL at diagnosis, but rises to 50 % if left untreated for > 8 weeks. Testicular relapse, once common, has fallen to < 2 % with contemporary high-dose methotrexate, yet remains a differential consideration in boys who develop painless testicular swelling after seemingly successful induction. 

Hyperleukocytosis—arbitrarily defined as white blood cell (WBC) count > 100 × 10⁹ L⁻¹—complicates 10 % of AML and 20 % of ALL. The metabolic syndrome encompasses tumour lysis, disseminated intravascular coagulation (DIC), and leukostasis. Pulmonary leukostasis produces hypoxaemia disproportionate to chest X-ray findings; cerebral leukostasis mimics stroke with dysphasia or hemianopia. Emergency leukapheresis lowers blast count by 30–50 % within 4 hours, but should never delay definitive chemotherapy. ATRA or arsenic trioxide must be started on clinical suspicion of acute promyelocytic leukaemia (APL) even before genetic confirmation, because early haemorrhagic death remains the dominant cause of induction failure in APL. 

Morphology and Cytochemistry

The peripheral blood smear is the single most cost-effective diagnostic test. Blasts are large, 12–20 µm, with high nuclear-to-cytoplasmic ratio, open chromatin, and prominent nucleoli. Auer rods—linear azurophilic granules—are pathognomonic for myeloid lineage and are seen in 60 % of AML, especially t(8;21) and t(15;17). Their absence never excludes AML, but their presence never occurs in ALL. Cytoplasmic vacuoles suggest monocytic differentiation (M4/M5), whereas homogeneous basophilia without granules favours ALL. The Meyer's index (proportion of smear area occupied by blasts) correlates with marrow blast percentage (r = 0.92) and can be calculated on a smartphone camera, offering a triage tool where flow cytometry is unavailable. 

Bone marrow aspiration remains mandatory. A dry tap implies fibrosis (acute panmyelosis with myelofibrosis) or packing with tightly cohesive blasts (APL). Touch imprints salvage morphology when aspiration fails. WHO 2022 retains the 20 % blast threshold for both AML and ALL, but acknowledges a biological continuum: patients with 10–19 % blasts and adverse genetics (e.g., complex karyotype) should be treated as AML, whereas those with t(12;21) or hyperdiploid B-ALL are treated as ALL even at 15 % blasts. Cytochemical stains persist in low-resource settings: myeloperoxidase (MPO) positivity in ≥ 3 % blasts confirms myeloid lineage; Sudan Black B parallels MPO but fades after 48 hours. Non-specific esterase (α-naphthyl acetate) highlights monocytic lineage, whereas periodic-acid–Schiff (PAS) block positivity supports B-ALL. 

Immunophenotyping

Flow cytometry is now indispensable. A 10-colour panel can resolve lineage, maturation stage, and aberrant antigen expression within 3 hours from sample receipt. The European LeukemiaNet (ELN) recommends a backbone of CD45, CD34, CD117, HLA-DR, MPO, CD13, CD33, CD14, CD64, CD15, CD11b for AML; and CD45, CD34, CD10, CD19, CD22, CD79a, CD3, CD5, CD7, CD4, CD8, TdT for ALL. Myeloid lineage is assigned when ≥ 10 % of blasts express MPO (intracellular) or two of CD13, CD33, CD117. Lymphoid lineage requires strong CD19 plus at least one of CD79a, CD22, CD10 (B-ALL) or surface CD3 (T-ALL). Aberrant antigens—CD7 on AML, CD13 on ALL—predict minimal residual disease (MRD) persistence and are integrated into risk scores. 

A practical challenge occurs when blasts co-express myeloid and lymphoid markers (“biphenotypic” or “mixed phenotype” acute leukaemia, MPAL). WHO 2022 adopts the EGIL score only as a guide; instead, it mandates that MPAL must show separate blast populations each satisfying lineage criteria, or a single population meeting both. Cytogenetics clarifies most dilemmas: t(9;22) is present in 30 % of MPAL and dictates tyrosine-kinase inhibitor (TKI) addition, whereas KMT2A rearrangement confers poor prognosis regardless of phenotype. 

Cytogenetics and Molecular Genetics

Conventional karyotype detects clonal abnormalities in 55 % of AML and 80 % of ALL, but requires 48–72 hours of culture. Fluorescence in-situ hybridisation (FISH) panels—PML-RARA, AML1-ETO, CBFB-MYH11, BCR-ABL1, KMT2A break-apart—yield same-day answers and are cost-effective when pre-test probability is high. Next-generation sequencing (NGS) has re-defined risk stratification. In AML, FLT3-ITD (allelic ratio ≥ 0.5), TP53 biallelic mutation, and ASXL1 frameshift are now formally “adverse” even with normal karyotype. Conversely, NPM1 mutation without FLT3-ITD is “favourable” provided the white-cell count is < 50 × 10⁹ L⁻¹. In ALL, IKZF1 plus (IKZF1plus) deletion profile and Ph-like signatures predict relapse despite MRD-negative status and justify upfront transplant. RNA sequencing can resolve cryptic fusions—e.g., NUP214-ABL1—that respond to dasatinib but are invisible on karyotype. 

Differential Diagnosis

The clinician’s first task is to decide whether circulating blasts truly represent leukaemia or are reactive. Extreme neutrophil left shift in sepsis can yield “stress” myeloid precursors with condensed chromatin and toxic granulation; these cells, however, retain CD16 and CD11b maturation antigens and lack CD34. Recovery from cytotoxic chemotherapy or granulocyte-colony stimulating factor (G-CSF) may produce transient CD34-positive blasts up to 8 %, but they disappear within 5–7 days. Aplastic anaemia, paroxysmal nocturnal haemoglobinuria (PNH), and myelodysplastic syndrome (MDS) all present with cytopenias yet marrow blasts < 5 %. Flow cytometry in PNH reveals glycosylphosphatidylinositol (GPI)-anchor deficiency in erythrocytes and granulocytes, whereas MDS shows characteristic dysplastic morphology and clonal cytogenetic changes—del(5q), del(20q), trisomy 8—without excess blasts. 

Viral illnesses deserve special caution. Infectious mononucleosis from Epstein–Barr virus (EBV) can generate atypical lymphocytes that mimic ALL, but these cells are polyclonal, CD3-positive without CD34, and resolve within 2 weeks. Cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), and SARS-CoV-2 have all been associated with transient marrow suppression and blast-like lymphocytosis; acute HIV seroconversion may present with pancytopenia and fever, requiring HIV RNA quantification. 

Solid tumours metastatic to marrow—neuroblastoma in children, small-cell lung cancer in adults—can masquerade as acute leukaemia. Neuroblastoma cells are smaller, form rosettes, and express CD56, chromogranin, synaptophysin without CD34. Carcinoma cells express cytokeratin, EMA, or TTF-1; they rarely exceed 20 % of marrow nucleated cells and are accompanied by fibrosis. Lymphomas, particularly Burkitt and lymphoblastic lymphoma, overlap extensively with ALL. Tissue biopsy showing effacement of architecture and high Ki-67 index > 95 % distinguishes Burkitt lymphoma, while mediastinal mass plus marrow blasts < 25 % favours T-lymphoblastic lymphoma rather than T-ALL. 

Autoimmune disorders—systemic lupus erythematosus, Felty’s syndrome—may yield cytopenias and splenomegaly, but antinuclear antibody (ANA) and anti-dsDNA titres are elevated, and marrow cellularity is either normal or hypercellular without blasts. Vitamin B12 or folate deficiency produces pancytopenia with megaloblastic changes; giant metamyelocytes and hypersegmented neutrophils contrast with leukaemic blasts, and vitamin replacement normalises counts within 4 weeks. Copper deficiency, increasingly recognised with excess zinc ingestion or bariatric surgery, mimics MDS with ring sideroblasts; serum copper < 70 µg dL⁻¹ and caeruloplasmin < 15 mg dL⁻¹ confirm the diagnosis, and copper repletion reverses cytopenias.   

Finally, drug-induced marrow aplasia or toxicity—linezolid, methotrexate, azathioprine—must be excluded by careful medication reconciliation. The temporal relationship (onset within 4–6 weeks of exposure), absence of blasts, and clinical recovery after drug withdrawal distinguish these entities from acute leukaemia. 

Discussion

The differential diagnosis of acute leukemias is no longer a static list but a dynamic algorithm that integrates clinical tempo, morphological clues, immunophenotypic signatures, and molecular lesions. Epidemiological data underscore the urgency: AML incidence is rising fastest in low-middle SDI regions where diagnostic capacity is weakest, and mortality gains in high-SDI countries have plateaued despite MRD-driven therapy intensification. The 2021 GBD estimate of 4.14 million DALYs translates into 113 life-years lost per 100 000 population—comparable to the burden of hypertensive heart disease. 

From a health-systems perspective, the greatest leverage lies in the first 24 hours after presentation. A district hospital with access to full blood count (FBC) and manual microscopy can rule in leukaemia with 90 % sensitivity if clinical suspicion is high; adding a 6-antigen flow panel raises sensitivity to 98 % and specificity to 94 %. Yet in LMICs, median time from symptom onset to accurate diagnosis remains 6 weeks, during which 12 % of patients die from bleeding or sepsis. Task-shifting—training general physicians to recognise cytopenic syndromes and tele-haematology review of smears—could avert one-third of early deaths at minimal cost. 

Advances in molecular taxonomy are beginning to refine differential reasoning. The recognition of germ-line predisposition—DDX41, CEBPA, RUNX1 mutations—explains familial clustering and mandates cascade testing, differentiating true acute leukaemia from inherited bone-marrow failure. Similarly, clonal haematopoiesis of indeterminate potential (CHIP) with DNMT3A or TET2 mutations can produce mild cytopenias and low-level blasts; longitudinal sequencing rather than immediate chemotherapy is appropriate, a nuance impossible without NGS. Conversely, the discovery of BCR-ABL1-like ALL masquerading as standard-risk B-ALL has narrowed the differential by revealing a hidden target, shifting management from chemotherapy alone to TKI inclusion. 

Limitations of our synthesis deserve acknowledgement. GBD data rely on modelling where cancer registries are absent; sub-Saharan Africa and parts of South-East Asia are under-represented, potentially underestimating true incidence. Survival figures quoted reflect period analysis, not real-time cohort follow-up, and may overstate recent progress. Finally, the pace of therapeutic innovation—particularly CD19- and CD22-directed immunotherapies—means that prognostic labels assigned today may be obsolete within 5 years. 

Conclusion

Acute leukemias embody the paradox of modern haematology: they are simultaneously the most curable and the most rapidly fatal of adult cancers. Their differential diagnosis spans the breadth of internal medicine—from nutritional deficiency to autoimmune disease, from infection to metastatic solid tumours—yet the common denominator is vigilant attention to blood counts and morphology. Epidemiological trends over the past five years warn of a widening survival chasm: while age-standardised mortality in high-SDI countries inches downward, absolute deaths continue to climb globally because of population ageing and unequal care access. The lens reveals that scientific progress (Methods, Results) must be coupled with health-system strengthening (Discussion) if the benefits of precision leukaemia therapy are to reach every patient who presents with unexplained cytopenias. Ultimately, the differential diagnosis of acute leukaemia is not a list to be memorised but a mindset—one that asks, “Could this be leukaemia?” every time fatigue, fever, or bleeding lacks an obvious cause, and that answers the question within hours, not weeks.

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