Acute lymphoblastic leukemia in children: symptoms and treatment

Acute lymphoblastic leukemia in children is a malignant disease of the hematopoietic system, in which immature lymphoid cells (blasts) proliferate uncontrollably in the bone marrow, crowding out normal hematopoietic lineages. Most commonly, this is a B-cell variant, while T-cell variants are less common. Modern diagnostics and treatment of ALL are based on agreed-upon international approaches: immunophenotyping with flow cytometry, cytogenetics, molecular testing, and assessment of minimal residual disease are mandatory. These elements, taken together, allow for accurate patient risk classification and tailored therapy to the tumor's genomics. [1]

Important advances have occurred in recent years. The World Health Organization's 5th edition classification identifies new genetically defined subtypes of B-lymphoblastic leukemia/lymphoma: ETV6::RUNX1, the DUX4-rearranged subtype, "Philadelphia-like," PAX5-alternative, and others. For the T-cell variant, subtypes are structured by driver (TLX1/TLX3/HOXA/LMO, early T-cell precursor). This isn't just academic fluff: subtypes change prognosis and treatment decisions in real-world practice. [2]

The standard treatment for children with ALL is multi-stage chemotherapy with central nervous system prophylaxis, dose escalation or de-escalation based on early response and minimal residual disease, and, in certain genetic variants, the addition of targeted and immune drugs. In refractory and relapsed cases, immunotherapy (blinazumab, inozumab ozogamicin) and cell therapy (chimeric antigen receptor T cells) are used. [3]

Thanks to the systematic implementation of these principles, 5-year survival rates for children aged 0-14 years in high-income countries have exceeded 90%. However, the global picture is uneven: in middle- and low-income countries, rates range from 22% to 79%, highlighting the importance of treatment routing and standardization. [4]

Code according to ICD-10 and ICD-11

In the International Classification of Diseases, 10th revision, the basic code for ALL is C91.0 "Acute lymphoblastic leukemia." Subcategories are used to specify remission status: C91.00 - "remission not achieved," C91.01 - "in remission," and C91.02 - "in relapse." These codes are used in clinical documentation, reporting, and insurance calculations. [5]

In the International Classification of Diseases, 11th revision, leukemias are classified under the "Neoplasms" section, combining topography and morphology in stem codes and allowing for post-coordination. For acute leukemias, the corresponding categories of Section 2B (malignant neoplasms of hematopoietic and lymphoid tissue) are used. Crucially, ICD-11 allows for the combination of "core" and "expander" codes for greater precision (behavior, molecular characteristics). The official ICD-11 browser is the primary source for coding. [6]

Table 1. Coding of ALL (ICD-10 and ICD-11)

Classifier	Code	Title / Explanation
ICD-10	C91.0	Acute lymphoblastic leukemia (general designation)
ICD-10 (subcategories)	C91.00 / C91.01 / C91.02	Accordingly: no remission / remission / relapse
ICD-11 (general principles)	Section 2B…	New model: unification of topography and morphology, post-coordination
Note	-	Morphological codes ICD-O-3 are also used for registers (for example, 9811/3, etc.)

Epidemiology

ALL is the most common malignant tumor in children. Globally, approximately 58,785 new cases of childhood leukemia were registered in 2021, of which ALL represents a significant proportion; the average global incidence is approximately 2.9 per 100,000 population (age-standardized). The incidence is slightly higher in boys than in girls. [7]

Age distribution is uneven: the peak incidence of ALL occurs between 2 and 5 years of age, which is associated with the characteristics of immune system maturation and "windows of vulnerability" for genomic events. Geographic differences reflect both treatment availability and possible ethnocultural genetic factors (for example, more frequent CRLF2 rearrangements in certain populations). [8]

Survival rates have improved dramatically over four decades and consistently exceed 90% at five-year follow-up in high-income countries. In resource-limited countries, the variability is large and is explained by delays in diagnosis, interruptions in treatment, and lack of access to drugs and support. These disparities represent a major challenge for global childhood oncology. [9]

Table 2. Epidemiology of childhood ALL (estimated)

Indicator	Meaning
Worldwide incidence (age-standardized)	≈2.9 per 100,000
Peak age	2-5 years
5-year survival in high-income countries	>90%
Survival range in low/middle income countries	22-79%

Reasons

ALL arises from the accumulation of genetic alterations in lymphoid precursors: translocations (e.g., ETV6::RUNX1), aneuploidies (hyper- and hypodiploidy), structural rearrangements (KMT2A rearrangements), and driver mutations (JAK-STAT, RAS cascade, etc.). These events disrupt differentiation and proliferation control, creating a "frozen" clone that gains a selective advantage. Many alterations are early embryonic, but a "second hit" is often required for clinical disease to develop. [10]

There are distinct etiologic subtypes. "Philadelphia-positive" ALL is defined by the presence of the BCR::ABL1 hybrid gene and is sensitive to tyrosine kinase inhibitors. "Philadelphia-like" (BCR::ABL1-like) is transcriptomically similar but heterogeneous in its drivers: rearrangements of the JAK-STAT axis (CRLF2, JAK1/2), as well as ABL class kinases (ABL1/2, PDGFRB, etc.). This explains the effectiveness of the corresponding targeted drugs in some children. [11]

Down syndrome-associated variants have a unique genetic landscape: CRLF2 rearrangements and JAK kinase mutations are more common, while changes typical of "non-specific" childhood ALL, such as ETV6::RUNX1 and high hyperdiploidy, are less common. This dictates the specifics of treatment and monitoring in this group. [12]

Exogenous factors play a much smaller role than in solid tumors. Risks from ionizing radiation and certain chemotherapy drugs have been described, but for the vast majority of children, a causal relationship with external influences is not evident. Inherited predisposition syndromes and intrauterine events are considered key. [13]

Risk factors

The largest established risk factor is Down syndrome: the risk of leukemia is 10-20 times higher than in the general population, and the molecular profile and tolerability of therapy are different. Such patients require specialized protocols. [14]

Other rare hereditary conditions are associated with an increased risk: ataxicotelangiectasia, neurofibromatosis type 1, DNA repair disorder syndromes, etc. Their contribution to overall morbidity is small, but for a particular family the risk is significant, and diagnosis requires genetic counseling. [15]

Biological factors that worsen the prognosis at diagnosis include unfavorable genetic aberrations (e.g., IKZF1-del and CRLF2/JAK cascades in Ph-like ALL), high leukocytosis, and a "slow" early response to therapy. Today, some of these risks are being "intercepted" by targeted and immune drugs. [16]

Table 3. Risk factors and clinical significance

Factor	Type	Clinical significance
Down syndrome (trisomy 21)	Hereditary	Increased risk of ALL; special genomics and tactics
DNA repair syndromes, NF1, etc.	Hereditary	Rare, require genetic counseling
CRLF2/JAK changes, IKZF1 del	Biological	Associated with Ph-like and worse outcome without targeted therapy
High leukocytosis at onset	Clinical	Sign of a higher risk of relapse

Pathogenesis

The underlying mechanism is a differentiation block and proliferative advantage of lymphoblasts. Classic translocations (ETV6::RUNX1, TCF3::PBX1), aneuploidies (high hyperdiploidy), and KMT2A rearrangements alter the functioning of transcription factors of early lymphoid development. This creates clones "stuck" at an early stage that are sensitive to antileukemic agents. [17]

Signaling pathways (JAK-STAT, RAS/MAPK, ABL-class) ensure the growth and survival of clones. Therefore, tyrosine kinase inhibitors (imatinib/dasitinib for BCR::ABL1) and JAK-axis inhibitors (in clinical trials for Ph-like) are a logical addition to chemotherapy in subgroups with corresponding drivers. [18]

Immune surveillance is impaired not only by the number and function of normal lymphocytes but also by the bone marrow microenvironment. This has practical implications: the depth of minimal residual disease after induction reflects not simply the "remnant cells" but the holistic biology of the tumor and its sensitivity. A threshold of 0.01% (10⁻⁴) is widely used as a clinically relevant benchmark for therapy escalation. [19]

In T-cell ALL, the pathogenesis is associated with the activation of transcriptional programs (TLX, LMO, HOXA), and early T-cell precursor (ETP-ALL) has mixed myeloid features and often a more aggressive course, which is taken into account in risk stratification. [20]

Symptoms

The picture consists of signs of suppressed normal hematopoiesis: pallor, weakness, shortness of breath during exertion (anemia), a tendency to bruise and bleed (thrombocytopenia), fever, and infections (neutropenia). Symptoms often develop over weeks, but in young children they can progress rapidly. Parents are alarmed by combinations of "frequently sick," "bruises without injury," and "became lethargic." [21]

Classic findings include generalized lymphadenopathy, hepatosplenomegaly, and bone pain. Sometimes the onset is leg pain and lameness, which is mistaken for an orthopedic problem. In the T-cell variant, a mediastinal mass with cough or shortness of breath is possible. [22]

Central nervous system damage manifests as headaches, vomiting, meningeal symptoms, and cranial nerve palsies, but is often detected only by lumbar puncture. Skin infiltrates and testicular enlargement are less common but require examination. [23]

It's important to remember: non-specific symptoms shouldn't delay a blood test. Any persistent fever without a focal point, bruising, severe fatigue, or bone pain in a child are reasons to order a complete blood count "today." [24]

Classification, forms and stages

The current nomenclature follows WHO-HAEM5. For the B-cell variant, subtypes based on genetics have been identified: ETV6::RUNX1, highly hyperdiploid, hypodiploid, BCR::ABL1, BCR::ABL1-like, DUX4-rearranged, MEF2D-rearranged, ZNF384-rearranged, PAX5alt/PAX5 p.P80R, etc. T-cell ALL includes subtypes based on transcription activators and a separate form of early T-cell precursor. [25]

Staging analogous to solid tumors is not used for leukemia; instead, extent of disease (including the central nervous system and testes), early response, and minimal residual disease are described. It is minimal residual disease after induction/consolidation that determines key treatment options. [26]

Table 4. B-lymphoblastic leukemia/lymphoma (WHO-HAEM5 subtype fragment)

Subtype	Example of notation
B-ALL with ETV6::RUNX1	t(12;21)
B-ALL highly hyperdiploid	≥51 chromosome
B-ALL BCR::ABL1 (Ph+)	t(9;22)
B-ALL BCR::ABL1-like	Ph-like, various JAK/ABL-class drivers

Table 5. Estimated prevalence at the onset of ALL

Region	What are we looking for?	How to fix
Bone marrow	Blast percentage	Morphology + flow
Central nervous system	Cells in cerebrospinal fluid/cytosis	Lumbar puncture
Testicles	Enlargement, infiltrate	Examination/ultrasound as indicated
Mediastinum (usually T-ALL)	Package of nodes/weight	X-ray/CT scan

Complications and consequences

At the beginning of treatment, the most common emergency is tumor lysis syndrome: rapid destruction of blasts causes hyperuricemia, hyperkalemia, hyperphosphatemia, and acute renal failure. Prevention includes hydration, allopurinol or rasburicase, and early electrolyte monitoring. [27]

Infectious complications associated with neutropenia are the leading cause of hospitalization; protocols for prophylaxis and prompt initiation of antibiotics during fever are necessary. Asparaginase-associated toxicities include hypersensitivity, pancreatitis, and thrombosis; monitoring and, if necessary, replacement or discontinuation are required. [28]

Long-term effects include anthracycline cardiotoxicity, neurocognitive and endocrine disturbances (especially after cranial irradiation), and second malignancies. Current protocols tend to avoid brain irradiation entirely or reserve it for limited indications. [29]

Relapse remains the main threat. The prognosis depends on the timing of relapse, location (bone marrow/central nervous system/combined), genetics, and the depth of response to salvage therapy. This determines the choice of immune and cellular therapies and the need for hematopoietic stem cell transplantation. [30]

When to see a doctor

You should seek medical attention "today" if you experience a combination of two or three of the following symptoms: persistent fever without a focal point, bruising or bleeding without injury, severe fatigue, pallor, bone pain, swollen lymph nodes, or weight loss. The only test that should not be delayed is a complete blood count. [31]

Immediate assistance is needed in case of signs of respiratory failure (suspected mediastinal mass), seizures, severe headache and vomiting with stiff neck (possible central nervous system damage), as well as symptoms of tumor lysis syndrome (lower back pain, weakness, arrhythmia). [32]

Children with inherited predisposition syndromes and their families benefit from pre-agreed plans for fever and cytopenia management, as well as contact information for a specialized center. This reduces the risk of delays and complications. [33]

The pediatrician/family physician should have a low threshold for referring for testing: “it is better to look at the blood smear one more time than to miss leukemia.” [34]

Diagnostics

The first step is a complete blood count (CBC) with a white blood cell count (WBC) and a peripheral blood smear. Anemia, thrombocytopenia, and leukocytosis or leukopenia are common; the presence of blasts in the smear confirms the suspicion, but their absence does not rule out ALL. Any significant cytopenia requires urgent consultation with a hematologist. [35]

The gold standard for confirmation is bone marrow aspiration with morphology and flow cytometry. Flow cytometry over 24-48 hours determines the immune phenotype (B-/T-cell), rules out mimics, and provides "anchor" markers for subsequent monitoring of minimal residual disease. Concurrently, material is collected for cytogenetics (karyotype/fluorescence in situ hybridization) and molecular panels (polymerase chain reaction/sequencing) for subtype determination. [36]

The third pillar is staging and evaluation of sanctuary sites. A lumbar puncture with cytology is mandatory before massive doses of steroids (if clinically safe) to diagnose central nervous system involvement. Imaging (chest X-ray, CT scan if indicated) is necessary if a mediastinal mass is suspected. In boys, the testicles are examined and, if indicated, tested. [37]

The fourth element is minimal residual disease: the depth of clone clearance after induction is a key predictor of relapse risk. A threshold of 0.01% (10⁻⁴) based on flow or molecular methods is widely used in protocols for escalation/de-escalation decisions. Minimal residual disease is then monitored at the end of consolidation and as indicated. [38]

Table 6. Diagnostic algorithm for suspected ALL

Stage	What are we doing?	For what
1	Complete blood count + smear	Rapid cytopenia/blast screening
2	Bone marrow aspiration + flow	Phenotype, confirmation, "anchor" for minimal residual disease
3	Cytogenetics/molecular tests	Risk stratification, targeted therapy
4	Lumbar puncture	Status of the central nervous system
5	Minimal residual disease control	Making decisions about risk and tactics

Differential diagnosis

The primary way to differentiate ALL from acute myeloid leukemia is by the immunophenotype (myeloid versus B/T lymphoid markers). Aplastic anemia produces cytopenias without blasts and without bone marrow infiltration, but with hypocellular marrow and rare blasts, repeated testing is necessary. [39]

Infectious mononucleosis, parvovirus, and other infections can produce atypical lymphocytes and cytopenias, but have a characteristic serologic profile and do not exhibit a monoclonal blast phenotype. When in doubt, flow and molecular testing are the final step. [40]

Lymphomas (especially lymphoblastic ones) can manifest with bone marrow involvement. The volume of infiltration and morphology are important here: if blasts in the marrow are <25%, lymphoma is more often considered; ≥25%, leukemia, although clinical management is generally similar. [41]

Skeletal pain and fever in a child are sometimes misdiagnosed as rheumatological pathology. A simple rule helps avoid mistakes: if persistent pain and cytopenias occur, always have the smear checked and refer the child to a hematologist. [42]

Treatment

Treatment consists of the following phases: remission induction, consolidation/intensification, maintenance therapy, and prevention of central nervous system damage. During the induction phase, combinations of glucocorticoids, vincristine, anthracycline, and asparaginase are used, with mandatory monitoring of the early response and minimal residual disease. The goal is to reduce blasts below detection thresholds and restore normal hematopoiesis. Risk factors are already established at this stage. [43]

Central nervous system prophylaxis today is primarily chemotherapy: regular intrathecal methotrexate administrations (sometimes in combination with cytarabine and glucocorticoids) and high-dose systemic methotrexate/cytarabine. Cranial irradiation has been minimized or eliminated in modern pediatric protocols; it is reserved for a select group of patients with strict indications, given the long-term risks. [44]

Risk stratification is based on clinical features (age, leukocytosis), genetics (e.g., BCR::ABL1, hypodiploidy, IKZF1-del), and minimal residual disease after induction/consolidation. A threshold of 0.01% often serves as a guideline for intensifying therapy and choosing transplantation in individual patients. This approach allows for "minimizing low-risk therapy and enhancing high-risk therapy," increasing the chance of cure and reducing late effects. [45]

In Philadelphia-positive ALL, a tyrosine kinase inhibitor (imatinib or dasitinib) is added to chemotherapy. Recent studies have shown that the combination of dasitinib with pediatric protocols provides high efficacy, with hematopoietic stem cell transplantation becoming less necessary in first remission if a deep response is achieved. [46]

Philadelphia-like (BCR::ABL1-like) is a heterogeneous subtype. For ABL class rearrangements, the addition of ABL inhibitors is being considered, and for JAK axis activation, JAK inhibitors (as part of clinical trials) are being considered. Genetic screening for these abnormalities is becoming standard practice at centers, as it changes the treatment plan from the onset. [47]

In children with minimal residual disease after induction or at the end of consolidation, blinazumatab (a bispecific anti-CD3×CD19 T-cell activator) is increasingly being used. The Children's Oncology Group randomized trial AALL1731 showed that adding two 28-day cycles of blinazumatab to chemotherapy in children with standard risk but an increased risk of relapse significantly improved relapse-free survival. This shifts the balance in favor of "chemo-minimization" while maintaining tumor control. [48]

In relapsed/refractory B-cell ALL, inosumab ozogamicin (anti-CD22 conjugate) is used. In 2024, the drug was approved for children ≥1 year of age with relapsed or refractory CD22-positive B-ALL; it demonstrates high remission and minimal residual disease eradication rates, but requires monitoring the risk of sinusoidal obstructive liver syndrome, especially during subsequent transplantation. [49]

CAR-T cell therapy (tesagenlecleucel, anti-CD19) has become an option for children and young adults with relapsed/refractory B-ALL. According to registration data, the remission rate within the first 3 months exceeds 80%, with a significant proportion achieving negative minimal residual disease. Toxicity (cytokine release syndrome, neurotoxicity) is manageable with modern protocols. This offers a chance for long-term remission in severely ill patients. [50]

T-cell ALL requires its own "basket" of options. Nelarabine is used in salvage regimens and, according to NCCN 2.2025, remains a significant element in relapsed/refractory disease; combinations with bortezomib, venetoclax, and new targets in certain subtypes are also being discussed. Hematopoietic stem cell transplantation is considered in high-risk and refractory cases. [51]

Maintenance therapy (usually 6-mercaptopurine and low-dose methotrexate for 1.5–2 years) remains the cornerstone for preventing late relapses. Quality of life and safety are ensured by adequate infection prophylaxis, thrombosis control with asparaginase, cardiac monitoring with anthracyclines, and limiting or avoiding cranial irradiation. After completion of treatment, monitoring programs for late effects are important. [52]

Table 7. Main components of therapy for childhood ALL

Component	What does it include?	Target
Induction	Combination chemotherapy + minimal residual disease control	Remission
CNS prevention	Intrathecal chemotherapy ± systemic high doses; radiation - rare	Prevent CNS relapse
Targeted/immune	Tyrosine kinase inhibitors in Ph+, blinazumb/inozumab in B-ALL	Deepen the answer
CAR-T	Anti-CD19 for R/R B-ALL	Long-term remission without transplantation in some patients

Prevention

There is no specific primary prevention for ALL. Early recognition of symptoms and prompt referral to a specialized center if suspected is the goal. Pediatricians and parents should be mindful of the "triad of concern": persistent fever, bruising/bleeding, and severe fatigue. [53]

Families with inherited predisposition syndromes require genetic counseling, education on "red flags," and a pre-formulated action plan for fever and cytopenias. This does not eliminate the risk, but it reduces delays in diagnosis. [54]

Tertiary prevention - reduction of late effects: avoidance of cranial irradiation if safe, limitation of cumulative doses of anthracyclines, cardio- and endocrine screening after completion of therapy, vaccination according to an individual schedule. [55]

Finally, participation in clinical trials is a way to obtain the best standards available today and contribute to improving them for future patients, especially in low- and middle-resource countries. [56]

Forecast (with table)

Overall, in high-income countries, the 5-year survival rate for children with ALL exceeds 90%, and the cure rate continues to increase due to targeted and immune-based approaches and therapies aimed at minimal residual disease. The main adverse factors are early relapse, bone marrow relapse, certain genetic variants (hypodiploidy, some KMT2A rearrangements), and persistent minimal residual disease. [57]

Philadelphia-positive no longer equals "transplant required": when linked to a tyrosine kinase inhibitor, some patients achieve deep remission without transplantation in first remission, especially with good control of minimal residual disease. [58]

In relapsed cases, immune- and cellular methods (blinazumab, inosumab, anti-CD19 CAR-T) significantly improve the chances. They allow for a negative minimal residual disease before transplantation or even avoid it altogether in some patients with long-term remission after CAR-T. [59]

Table 8. Integrated forecast assessment

Situation	5-year survival / comments
First remission, high-income countries	>90%
Early bone marrow relapse	Significantly worse; requires immune/cellular therapy
Ph+ in modern treatment	High chances of remission with TKI; HSCT is individual
R/R B-ALL with access to CAR-T	High frequency of deep remissions

Additional pivot tables

Table 9. Mandatory laboratory tests at the start

Block	Test	For what
General clinical	General blood test, smear	Cytopenia/blast screening
Biochemistry	Lactate dehydrogenase, uric acid, creatinine, electrolytes	Tumor mass, risk of lysis
Coagulation	International normalized ratio, fibrinogen	Risk of bleeding
Infections	Viral hepatitis, human immunodeficiency virus	Safety of therapy

Table 10. Minimal residual disease: thresholds and methods

Method	Sensitivity	Decision-making threshold
Flow cytometry	Up to 10⁻⁴	≥0.01% - alarming level
Polymerase chain reaction/NGS tracking	Up to 10⁻⁵-10⁻⁶	Confirming the depth of the response

Table 11. Targeted/immune drugs in children (short reference)

Preparation	Goal/target	Where is it used?
Imatinib/dasitinib	BCR::ABL1	Ph+ debut/from the first cycles
Blinazumab	CD19×CD3	Minimal residual disease+, relapsed/refractory
Inosumab ozogamicin	CD22	Relapsed/refractory B-ALL (approved for children from 2024)
CAR-T (tesagenlecleucel)	CD19	Relapsed/refractory B-ALL before age 25

Table 12. When to discuss hematopoietic stem cell transplantation

Context	Comment
Early bone marrow relapse	Often indicated after achieving remission
Retained minimal residual disease at the end of consolidation	Consider, especially in case of unfavorable genetics
Refractory to 1st line	After immune/cellular "bridge therapy"

Table 13. Toxicity and monitoring

Risk	What are we doing?
Lysis syndrome	Hydration, allopurinol/rasburicase, electrolyte monitoring
Infections in neutropenia	Prevention, "antibiotics on call" for fever
Asparaginase: pancreatitis/thrombosis	Monitoring, replacement/cancellation according to indications
Late effects	Cardiac screening, cognitive/endocrine monitoring

FAQ (frequently asked questions)

1) Is cranial irradiation always necessary for ALL? No. Modern protocols for children have almost completely abandoned cranial irradiation, relying on intrathecal and systemic chemotherapy. Irradiation is reserved for very specific indications due to the risk of late effects. [60]

2) What does "minimal residual disease of 0.01%" mean? This is 1 blast per 10,000 normal cells. This level after induction is a sign of increased risk and a reason to intensify treatment or add immune-based therapies; specific decisions are made by a panel of experts. [61]

3) Is it true that children with the Philadelphia chromosome now require transplants less frequently? Yes. The combination of pediatric protocols with tyrosine kinase inhibitors provides high efficacy; in deep remission, the question of transplantation in the first remission is decided on an individual basis. [62]

4) What has changed in the first-line setting for standard-risk patients? The addition of blinazumb to chemotherapy in some children with standard risk but an increased risk of relapse improves relapse-free survival and is becoming the new norm in protocols. [63]

5) When is CAR-T considered? For relapsed/refractory B-ALL in children and young adults under 25 years of age, especially when multiple lines have failed. Deep remission rates are high, but a commitment to managing cytokine release syndrome and neurotoxicity is required. [64]