Pediatrics (System-Integrated)

Pediatric leukemia: ALL workup and presentation

Clinical Overview and When to Suspect Pediatric ALL

— Peak incidence age 2–5 years; second smaller peak in adolescence

— Slight male predominance; higher incidence in Hispanic and White children

— B-cell precursor ALL ~85%, T-cell ALL ~10–15%

— Persistent unexplained fever >1–2 weeks without clear source

— Pallor, fatigue, or new-onset bruising/petechiae

— Bone or joint pain, refusal to bear weight, limp (especially nocturnal pain waking child)

— Lymphadenopathy + hepatosplenomegaly

— Pancytopenia or bicytopenia with blasts on CBC/smear

— Anterior mediastinal mass with respiratory symptoms (T-ALL)

— Down syndrome (10–20× risk; both ALL and AML)

— Neurofibromatosis type 1, Li-Fraumeni, ataxia-telangiectasia, Bloom syndrome

— Prior chemotherapy/radiation

— Monozygotic twin of an affected infant

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, accounting for ~25% of childhood cancers and ~75% of childhood leukemias

Pathophysiology: clonal proliferation of lymphoid precursors crowding out normal marrow → pancytopenia and tissue infiltration (nodes, spleen, liver, CNS, testes, mediastinum in T-ALL)

When to suspect in a child presenting with:

Risk-increasing conditions (counsel families, lower threshold to evaluate):

Step 3 management: A child with >2 weeks of fatigue, bruising, and bone pain needs a CBC with differential and peripheral smear as the first outpatient step — do not "watch and wait." If any cytopenia in ≥2 lineages, blasts on smear, or unexplained pancytopenia, refer urgently to pediatric hematology/oncology the same day rather than scheduling routine follow-up.

Board pearl: Bone pain that wakes a child at night and is unrelieved by NSAIDs, combined with even mild cytopenias, is a classic ALL stem — far more specific than isolated lymphadenopathy.

Presentation Patterns and Key History

— Anemia: progressive pallor, fatigue, decreased play/activity tolerance, tachycardia, irritability in toddlers

— Thrombocytopenia: easy bruising, petechiae (especially on lower extremities/pressure points), epistaxis, gum bleeding, menorrhagia in adolescents

— Neutropenia: recurrent or prolonged fevers, mouth sores, perirectal pain, atypical infections

— Bone/joint pain in ~40%; often migratory, may mimic growth pains, JIA, or osteomyelitis; nocturnal pain and limp are red flags

— Abdominal fullness or early satiety (hepatosplenomegaly)

— Painless lymphadenopathy, often cervical/supraclavicular

— T-ALL: dyspnea, orthopnea, cough, facial swelling from anterior mediastinal mass → SVC syndrome risk

— CNS involvement at diagnosis (~3%): headache, vomiting, cranial nerve palsies (especially CN VII), papilledema

— Testicular enlargement (painless) — uncommon at diagnosis, more often at relapse

— Recent viral illnesses (mononucleosis, parvovirus can mimic)

— Medication exposures (drug-induced cytopenias)

— Family history of cancers, consanguinity, immunodeficiency syndromes

— Constitutional B-symptoms (fevers, weight loss, drenching night sweats)

— Travel/TB exposure (differential for mediastinal mass and adenopathy)

Marrow failure triad drives most presenting symptoms — ask specifically about each:

Infiltrative symptoms — distinct historical clues:

Tempo of illness: symptoms typically evolve over 2–6 weeks; an acute fulminant presentation suggests infection/sepsis or AML rather than ALL

Key historical screening questions:

Key distinction: Acute leukemia vs. ITP — both cause petechiae and bruising, but ITP has isolated thrombocytopenia with otherwise normal CBC and no hepatosplenomegaly, lymphadenopathy, or bone pain. Any "ITP" stem with cytopenias in 2 lineages, organomegaly, or bone pain is leukemia until bone marrow proven otherwise — do not give steroids empirically, as it can partially treat and obscure ALL diagnosis.

Board pearl: Steroids before tissue diagnosis = classic Step 3 wrong answer in suspected leukemia.

Physical Exam Findings and Hemodynamic Assessment

— Tachycardia disproportionate to fever → severe anemia

— Hypotension or narrow pulse pressure → sepsis from neutropenia, or rare cardiac tamponade from pericardial leukemic infiltration

— Hypoxia, stridor, positional dyspnea → mediastinal mass (do not lay flat for sedation)

— Hypertension → renal infiltration or tumor lysis–related changes

— Pallor of conjunctivae, palmar creases

— Petechiae (non-blanching, pinpoint), ecchymoses in non-traumatic distribution

— Gingival hyperplasia (more AML M4/M5, but possible)

— Chloromas/leukemia cutis (rare in ALL; more AML)

— Firm, non-tender, mobile lymphadenopathy; supraclavicular nodes are always pathologic in children

— Splenomegaly in ~60%, hepatomegaly in ~50%; document size in cm below costal margin

— Abdominal mass may also suggest neuroblastoma, Wilms, lymphoma

— Funduscopy for papilledema or retinal hemorrhages

— Cranial nerve exam (especially CN VII palsy suggests CNS leukemia)

— Meningismus

— Testicular exam in boys — unilateral painless enlargement

General appearance: ill-appearing, pale, tachycardic; assess weight loss, growth percentiles, and Tanner stage in adolescents

Vital signs and hemodynamics:

Skin/mucosa:

Lymphatics and abdomen:

HEENT/Neuro:

Musculoskeletal: point tenderness over long bones (especially proximal tibia), refusal to bear weight, joint effusions

Respiratory: assess for tracheal deviation, decreased breath sounds, SVC signs (facial plethora, neck vein distention, upper extremity edema)

Step 3 management: In a child with new mediastinal mass and stridor, avoid supine positioning and avoid sedation for imaging — get an upright CXR first, then echo to assess for pericardial effusion, before any anesthesia decisions. Anesthesia-induced loss of tone can collapse the airway and cause arrest.

CCS pearl: Order CBC, type & screen, coags, electrolytes including phosphorus/uric acid, and CXR within the first virtual hour of any suspected leukemia presentation.

Diagnostic Workup — Initial Labs, Imaging, Biomarkers

— WBC may be low, normal, or markedly elevated (>50,000 = hyperleukocytosis, a leukostasis risk)

— Anemia (normocytic, low reticulocyte count) in ~80%

— Thrombocytopenia in ~75%

— Blasts on smear are diagnostic of acute leukemia — but absence does not rule it out (aleukemic leukemia)

— Uric acid, LDH, phosphorus, potassium, calcium, BUN/creatinine

— Elevated LDH and uric acid are hallmarks of high cell turnover

— Hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia = tumor lysis syndrome (TLS), may occur spontaneously before therapy

— CXR (PA and lateral) — mandatory to evaluate for mediastinal mass before any sedation

— Abdominal US if organomegaly unclear

— Testicular US if asymmetric enlargement

— Avoid routine CT until oncology directs workup

— Hepatitis B/C, HIV serologies (pre-chemo)

— Pregnancy test in post-menarchal females

— Echocardiogram (baseline LVEF before anthracyclines)

— Varicella titer

CBC with differential and manual peripheral smear — the single most important first test

Chemistries and tumor lysis labs — obtain before any treatment:

Coagulation studies: PT/PTT, fibrinogen, D-dimer — DIC can occur (more common in AML M3/APL, but screen all)

Type and screen, blood and platelet products availability

Infectious workup if febrile: blood cultures × 2, urinalysis/culture, CXR; broad-spectrum antibiotics for febrile neutropenia

Imaging:

Other baseline:

Key distinction: TLS vs. SIADH vs. acute kidney injury — TLS has the specific tetrad (↑K, ↑PO4, ↑uric acid, ↓Ca with secondary AKI). Begin IV hydration (2× maintenance, no potassium) and allopurinol or rasburicase immediately upon suspecting leukemia with high tumor burden — don't wait for diagnostic confirmation.

Board pearl: Rasburicase is preferred over allopurinol when uric acid is already elevated or WBC >100K; contraindicated in G6PD deficiency (causes hemolysis and methemoglobinemia).

Diagnostic Workup — Advanced and Confirmatory Studies

— Performed by pediatric heme/onc, usually posterior iliac crest

— Diagnosis of ALL requires ≥25% lymphoblasts in marrow (vs. lymphoma: <25%)

— Sent for morphology, flow cytometry, cytogenetics, FISH, molecular studies

— B-ALL markers: CD19, CD20, CD22, CD79a, TdT, CD10 (common ALL antigen)

— T-ALL markers: CD2, CD3 (cytoplasmic), CD5, CD7, TdT

— Distinguishes ALL from AML (myeloperoxidase+, CD13/33+) and from lymphoma

— Favorable: hyperdiploidy (>50 chromosomes), ETV6-RUNX1 (t(12;21))

— Unfavorable: hypodiploidy (<44), KMT2A (MLL) rearrangements — especially in infants, Ph+ ALL (BCR-ABL1, t(9;22)), iAMP21, Ph-like ALL

— TCF3-PBX1 (t(1;19)) — intermediate

— CNS1: no blasts; CNS2: <5 WBC with blasts; CNS3: ≥5 WBC with blasts or cranial nerve findings

— Often combined with first dose of intrathecal methotrexate — done by oncology after platelet correction (>50K) and coag normalization

Bone marrow aspiration and biopsy — the definitive diagnostic test

Flow cytometry / immunophenotyping — distinguishes lineage and maturity:

Cytogenetics and molecular profiling — drives risk stratification:

Lumbar puncture with intrathecal chemotherapy — performed at diagnosis to assess CNS involvement:

Minimal residual disease (MRD) measured by flow or PCR at end of induction (day 29) — strongest prognostic factor; MRD <0.01% = excellent prognosis

Other: HLA typing if high-risk (potential transplant), fertility counseling/sperm banking in pubertal males, baseline neuropsychological assessment

Step 3 management: Do not perform LP before correcting thrombocytopenia and coagulopathy; traumatic LP with blasts contaminating CSF worsens prognosis and forces reclassification — transfuse platelets to >50K and reverse coagulopathy first.

Board pearl: A child with >25% lymphoblasts in marrow = ALL; <25% with a tissue mass = lymphoblastic lymphoma — same biology, different staging.

Risk Stratification and First-Line Management Logic

— Standard risk: age 1–<10 years AND WBC <50,000/μL at diagnosis

— High risk: age <1 or ≥10 years, OR WBC ≥50,000, OR CNS3 disease, OR testicular involvement, OR adverse cytogenetics, OR poor early response (MRD positive at day 29)

— Induction (~4 weeks): vincristine, glucocorticoid (dexamethasone or prednisone), PEG-asparaginase, ± anthracycline (daunorubicin) in high risk → goal is morphologic remission and MRD-negative status

— Consolidation: cyclophosphamide, cytarabine, 6-mercaptopurine

— Interim maintenance: high-dose methotrexate with leucovorin rescue

— Delayed intensification: re-induction-like block

— Maintenance (~2 years): daily 6-MP, weekly methotrexate, monthly vincristine + steroid pulses, ongoing intrathecal therapy

NCI/Rome risk classification for B-ALL — guides treatment intensity:

T-ALL — generally treated as high risk regardless of age/WBC

Infant ALL (<1 year) — uniquely poor prognosis, especially with KMT2A rearrangements; treated on separate protocols

Down syndrome ALL — modified protocols due to chemotherapy toxicity (methotrexate sensitivity, mucositis, infection risk); generally intermediate prognosis

Treatment phases (COG-style backbone) — span ~2–3 years total:

CNS-directed therapy: intrathecal methotrexate (± cytarabine, hydrocortisone) throughout treatment; cranial radiation now largely avoided due to neurocognitive late effects — reserved for CNS3 or relapse

Ph+ ALL: add tyrosine kinase inhibitor (imatinib or dasatinib) to chemotherapy backbone — dramatic improvement in outcomes, often avoids transplant in first remission

Step 3 management: Risk group determines intensity, but every newly diagnosed child gets enrollment in a clinical trial offered, fertility counseling for pubertal patients, and a central venous access device (port or tunneled line) placed early for the prolonged regimen.

Board pearl: 5-year overall survival in pediatric ALL now exceeds 90% — one of oncology's great success stories.

Pharmacotherapy — First-Line Drug Regimen Details

— Vincristine: peripheral and autonomic neuropathy (constipation, foot drop, jaw pain, SIADH). Dose-cap at 2 mg. Vesicant — extravasation causes severe tissue injury.

— Glucocorticoids (dexamethasone or prednisone): hyperglycemia, hypertension, mood/behavior changes, avascular necrosis (especially adolescents on dex), infection risk, weight gain, adrenal suppression — requires stress-dose steroids during illness/surgery

— PEG-asparaginase: hypersensitivity/anaphylaxis, pancreatitis, hyperglycemia, hyperammonemia, thrombosis (CSVT especially), hypofibrinogenemia and coagulopathy — monitor fibrinogen and antithrombin

— Daunorubicin (anthracycline): cardiotoxicity (cumulative-dose dependent), red urine, myelosuppression, mucositis, vesicant

— Methotrexate (high-dose IV and intrathecal): mucositis, nephrotoxicity, hepatotoxicity, neurotoxicity (stroke-like syndrome). Leucovorin rescue required; alkalinize urine, monitor levels. Avoid TMP-SMX, NSAIDs, PPIs during high-dose MTX

— 6-Mercaptopurine (6-MP): hepatotoxicity, myelosuppression. TPMT and NUDT15 genotype guides dosing — poor metabolizers get severe pancytopenia. Take on empty stomach, avoid with milk

— Cyclophosphamide: hemorrhagic cystitis (give mesna and hydration), SIADH, secondary malignancy (later AML)

— Cytarabine: cerebellar toxicity at high doses, conjunctivitis (give prophylactic steroid eye drops), "ara-C syndrome" (fever, rash, malaise)

— PJP prophylaxis: TMP-SMX (3 days/week) throughout therapy and 3–6 months after

— Antifungal prophylaxis in high-risk phases

— Antiemetics (ondansetron), allopurinol/rasburicase during induction

— Growth factor (G-CSF) selectively per protocol

Induction agents and their signature toxicities — Step 3 loves these pairings:

Consolidation and beyond:

Supportive medications — always on the MAR:

CCS pearl: When a child on maintenance presents with fever and ANC <500, order blood cultures, CBC/diff, CMP, lactate, UA/UCx, CXR, then start empiric cefepime (or pip-tazo) within 60 minutes — do not wait for cultures.

Procedures and Oncologic Emergencies

— Port-a-cath preferred for outpatient maintenance; tunneled Broviac/Hickman for induction or BMT

— Risks: infection (CLABSI), thrombosis, mechanical failure

— Sterile technique and antibiotic lock therapy for line infections; remove for fungemia, S. aureus, persistent bacteremia

— Very high-risk features (hypodiploidy, persistent MRD)

— Induction failure or early relapse

— Selected Ph+ ALL (less common in TKI era)

— Generally allogeneic matched sibling or unrelated donor

— Tumor lysis syndrome → IV hydration, rasburicase/allopurinol, electrolyte management; avoid calcium replacement unless symptomatic (precipitates calcium phosphate)

— Hyperleukocytosis → cytoreduction, hydration, avoid transfusing PRBCs above Hgb 8–9

— Mediastinal mass → avoid supine positioning and general anesthesia until shrinkage

— Febrile neutropenia → empiric antibiotics within 1 hour

— SVC syndrome → head elevation, oxygen, urgent oncology consult, emergent steroids/chemo to shrink mass

Central venous access — required for prolonged chemotherapy

Bone marrow procedures: aspirate + biopsy at diagnosis, end-induction (day 29), and for relapse monitoring

Lumbar punctures: serial therapeutic LPs with intrathecal chemo throughout protocol — perform under sedation/anesthesia; ensure platelets >50K

Leukapheresis: for symptomatic hyperleukocytosis (WBC >100K with leukostasis: hypoxia, mental status changes, priapism) — bridge to chemotherapy. Avoid RBC transfusion in this setting (increases viscosity).

Hematopoietic stem cell transplantation (HSCT) — reserved for:

CAR-T cell therapy (tisagenlecleucel) for relapsed/refractory B-ALL in patients ≤25 — anti-CD19; toxicities: cytokine release syndrome (CRS) (treat with tocilizumab) and neurotoxicity (ICANS)

Oncologic emergencies on Day 1:

Step 3 management: In TLS, never give IV calcium unless the patient is symptomatic from hypocalcemia (tetany, seizures) because it precipitates with phosphate → AKI worsens.

Special Populations — Renal, Hepatic, and Comorbidity Considerations

— Methotrexate is renally cleared — delayed clearance causes prolonged toxicity (mucositis, myelosuppression, AKI). Monitor levels, continue leucovorin until level <0.1 μM; glucarpidase rescue if level remains high

— Avoid nephrotoxins: NSAIDs, aminoglycosides if possible, IV contrast unless essential

— Dose-adjust carboplatin, etoposide, cyclophosphamide per CrCl

— Vincristine is hepatically metabolized — reduce dose if bilirubin elevated

— 6-MP and methotrexate commonly cause transaminitis; usually continue with monitoring unless severe (ALT >10× ULN or bilirubin >3)

— Anthracyclines require dose reduction in hyperbilirubinemia

— Hepatic veno-occlusive disease (SOS) more common post-HSCT — treat with defibrotide

— Obtain baseline echo before anthracyclines; serial monitoring during and after therapy

— Anthracycline cardiotoxicity is cumulative; avoid >300 mg/m² when possible

— Dexrazoxane cardioprotection in high-risk regimens

— Children with congenital heart disease need cardio-oncology co-management

— Better outcomes when treated on pediatric protocols (more asparaginase, more steroids, less transplant) than adult regimens

— Higher rates of osteonecrosis, thrombosis, pancreatitis on pediatric protocols — monitor accordingly

Renal impairment — present at diagnosis from TLS, leukemic infiltration, or uric acid nephropathy:

Hepatic impairment — from leukemic infiltration, TPN, drugs, viral hepatitis:

Cardiac comorbidity / pre-existing dysfunction:

Older adolescents and young adults (AYA, 15–39):

Obesity: increased risk of asparaginase-related complications (pancreatitis, hyperglycemia, thrombosis) and dosing challenges

Trisomy 21: hypersensitive to methotrexate (mucositis, myelosuppression) and high infection risk — protocols often reduce MTX dose

Key distinction: Pediatric-inspired protocols beat adult protocols in AYA ALL — a Step 3 stem with a 17- or 19-year-old should be referred to a pediatric oncology or AYA-specialized center, not started on adult regimens.

Special Populations — Pregnancy, Infants, and Genetic Syndromes

— Often presents with very high WBC, hepatosplenomegaly, CNS disease

— KMT2A (MLL) rearrangement in ~80% — poor prognosis

— Treated on infant-specific protocols (Interfant) with reduced anthracyclines and modified intrathecal therapy

— High rates of toxicity; consider HSCT in highest-risk

— Maternal history relevant — KMT2A leukemia in infants has been associated with maternal topoisomerase II inhibitor exposure (flavonoids, some medications)

— Always obtain pregnancy test in post-menarchal females before chemo

— Pregnancy in adolescent ALL patient: 1st trimester chemo causes teratogenicity; 2nd/3rd trimester treatment is feasible with multidisciplinary care; methotrexate is contraindicated

— Counsel about contraception during and 6–12 months after therapy

— Fertility preservation: sperm banking in pubertal males before therapy; ovarian tissue cryopreservation is experimental in prepubertal females, oocyte retrieval in postmenarchal

— 10–20× higher leukemia risk; both transient abnormal myelopoiesis (TAM) in neonates and later AML/ALL

— DS-ALL: increased treatment-related mortality from infection and mucositis

— Avoid high-dose methotrexate where possible; aggressive infection prophylaxis

— Li-Fraumeni (TP53): avoid radiation when possible

— Ataxia-telangiectasia: radiation- and alkylator-sensitive

— NF1: increased AML/JMML > ALL

— Bloom, Fanconi anemia: chemotherapy hypersensitivity

Infant ALL (<12 months) — distinct biologic and clinical entity:

Adolescents (and pregnancy considerations):

Down syndrome:

Cancer predisposition syndromes (consider genetic counseling):

Siblings/twins: monozygotic twin of a child with ALL diagnosed in infancy has very high concordance risk; older twins have lower but still elevated risk — monitor with periodic CBC if symptomatic

Step 3 management: Always document fertility counseling and preservation discussion in adolescent oncology charts — failure to offer it is a recognized quality-of-care gap and a Step 3 patient-safety theme.

Board pearl: Children with Down syndrome ALL need modified chemotherapy and more aggressive supportive care — outcomes are improving but treatment-related mortality remains higher.

Complications and Adverse Outcomes

— Tumor lysis syndrome: AKI, arrhythmia, seizures from electrolyte derangements

— Febrile neutropenia and sepsis — leading cause of treatment-related mortality

— Typhlitis (neutropenic enterocolitis): RLQ pain, fever, bloody diarrhea in profoundly neutropenic child; manage with bowel rest, broad-spectrum antibiotics, surgery rarely

— Invasive fungal infections (Aspergillus, Candida, Mucor) during prolonged neutropenia

— Viral reactivation: HSV, VZV, CMV, EBV; disseminated varicella can be fatal

— PJP pneumonia if prophylaxis missed

— Asparaginase: anaphylaxis, pancreatitis, thrombosis (especially CSVT), hyperglycemia, hepatic dysfunction

— Vincristine: SIADH, severe neuropathy, ileus

— Steroids: avascular necrosis of femoral head (adolescents), hyperglycemia, hypertension, mood disorders, AVN, cataracts long-term

— Methotrexate: stroke-like encephalopathy, nephrotoxicity, leukoencephalopathy

— Anthracyclines: cardiomyopathy (early and late)

— Cyclophosphamide: hemorrhagic cystitis, infertility

— Marrow relapse most common; treatment intensified, often with HSCT

— CNS relapse: requires increased intrathecal therapy ± cranial radiation

— Testicular relapse: bilateral testicular radiation + systemic therapy

— Early relapse (<36 months from diagnosis) = worse prognosis

— Neurocognitive impairment (attention, processing speed) — especially after cranial radiation

— Cardiomyopathy from anthracyclines

— Endocrine: short stature, infertility, hypothyroidism, early menopause

— Secondary malignancies: t-AML, brain tumors (post-radiation), thyroid cancer

— Osteonecrosis, osteoporosis

— Psychosocial: anxiety, depression, PTSD, educational/vocational impact

Acute, treatment-related:

Drug-specific:

Relapse:

Long-term/late effects (lifelong survivorship issues):

CCS pearl: A child on therapy presenting with new focal neurologic deficit needs emergent non-contrast head CT to rule out hemorrhage, then MRI/MRV to evaluate for cerebral sinus venous thrombosis (asparaginase complication) — start anticoagulation if confirmed, in consultation with oncology.

When to Escalate Care — ICU, Consult, Inpatient Triage

— Hemodynamic instability or septic shock with febrile neutropenia

— Respiratory failure (mediastinal mass, pneumonia, ARDS from leukostasis)

— Severe TLS with refractory hyperkalemia, arrhythmia, or need for renal replacement therapy

— Altered mental status from CNS leukemia, hemorrhage, leukostasis, or PRES

— DIC with bleeding

— Severe CRS post CAR-T (grade 3–4)

— SVC syndrome with airway compromise

— Any child with suspected leukemia (blasts on smear, unexplained pancytopenia, leukemia with organomegaly)

— Do not start steroids, transfuse aggressively, or delay transfer

— Transfer to a pediatric tertiary center with oncology services

— All newly diagnosed leukemia for diagnostic workup, TLS prophylaxis, and initiation of induction

— Febrile neutropenia in any phase

— Severe mucositis requiring TPN or IV opioids

— Uncontrolled vomiting/dehydration during chemo

— High-dose methotrexate administration (for hydration and leucovorin monitoring)

— Surgery: line placement, biopsy of nodes if needed

— Interventional radiology: tunneled access, drainage of effusions

— Cardiology: baseline and surveillance echo, cardiomyopathy

— Infectious disease: complex fevers, fungal infections

— Palliative care: introduce early in high-risk cases, not just end-of-life

— Psychology/Child Life: anxiety management, procedural support, school reentry

— Afebrile, hemodynamically stable

— Tolerating PO with stable electrolytes

— Reliable central access, family education completed on neutropenic precautions and fever return precautions

— Outpatient infusion clinic follow-up arranged within days

Immediate ICU admission criteria:

Urgent pediatric heme/onc consultation — same day, before treatment:

Inpatient admission (ward-level) typically required for:

Other key consults:

Discharge criteria from induction admission:

Step 3 management: Any febrile child on chemotherapy is assumed neutropenic until proven otherwise — go straight to blood cultures and empiric antibiotics within 60 minutes; do not wait for CBC results before starting.

Key Differentials — Other Hematologic/Oncologic Causes

— Older children/teens or infants (especially <2)

— Auer rods, myeloperoxidase+ blasts, gum hyperplasia, leukemia cutis, chloromas

— APL (M3): t(15;17), severe DIC at presentation — treat with ATRA urgently

— Cytogenetics distinguish from ALL; flow cytometry definitive

— Lymphoblastic lymphoma: same cells as T-ALL but <25% marrow blasts, often with mediastinal mass and adenopathy

— Burkitt (mature B-cell) lymphoma: jaw mass (endemic) or abdominal mass (sporadic), extreme TLS risk, "starry sky" on histology, MYC translocation

— Hodgkin lymphoma: painless cervical/supraclavicular adenopathy, B symptoms, Reed-Sternberg cells, bimodal age (15–35 and >50)

— Pancytopenia with hypocellular marrow, no blasts; differential: Fanconi anemia (short stature, thumb anomalies, café-au-lait), Diamond-Blackfan

— Treat with immunosuppression or HSCT

— JMML: <4 years old, monocytosis, hepatosplenomegaly, NF1 association

— RAS pathway mutations

— Marrow infiltration possible — biopsy shows rosettes, not blasts

— Adrenal mass, raccoon eyes, opsoclonus-myoclonus, elevated urine VMA/HVA

— Rhabdomyosarcoma, Ewing sarcoma, retinoblastoma — bone marrow may show small round blue cells, not lymphoblasts; immunohistochemistry distinguishes

Acute myeloid leukemia (AML):

Lymphoma:

Aplastic anemia:

Myelodysplastic syndrome / JMML:

Neuroblastoma (in young child with bone pain and pancytopenia):

Solid tumor with marrow infiltration:

Key distinction: ALL vs. lymphoblastic lymphoma is purely a percentage of marrow blasts — ≥25% = leukemia; <25% with extramedullary tumor = lymphoma. Biology and treatment overlap heavily, but staging differs.

Board pearl: AML with t(15;17) (APL) is the oncologic emergency where ATRA is started on clinical suspicion alone, before final cytogenetic confirmation, because untreated APL kills by DIC and intracerebral hemorrhage within days.

Key Differentials — Non-Oncologic Mimics

— Isolated thrombocytopenia, often post-viral

— Otherwise well child, no hepatosplenomegaly, no lymphadenopathy, no anemia, no bone pain

— Smear: low platelets only, normal WBC and Hgb

— Key teaching: confirm before steroids — bone marrow biopsy if any atypical features

— Fever, fatigue, exudative pharyngitis, posterior cervical adenopathy, splenomegaly

— Atypical lymphocytes (reactive, not blasts) — larger, abundant blue cytoplasm

— Heterophile antibody positive, transaminitis common

— Smear and flow distinguish

— Joint swelling, morning stiffness, fevers (systemic onset) — overlaps with leukemia bone pain

— Always check CBC and LDH before starting steroids for "JIA" — leukemia can present as polyarthritis

— Smear and marrow if any cytopenia or elevated LDH

— Focal bone/joint tenderness, fever, elevated ESR/CRP

— MRI and aspirate distinguish; usually no pancytopenia

— Persistent fever, hepatosplenomegaly, cytopenias, hyperferritinemia (>500, often >10,000), hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis on marrow

— Can be primary (genetic) or secondary (EBV, malignancy itself)

Idiopathic thrombocytopenic purpura (ITP):

Infectious mononucleosis (EBV):

Other viral suppression: parvovirus B19 (aplastic crisis), CMV, HHV-6, hepatitis viruses — transient cytopenias

Juvenile idiopathic arthritis (JIA):

Osteomyelitis / septic arthritis:

Hemophagocytic lymphohistiocytosis (HLH):

Nutritional deficiencies: severe B12, folate, iron deficiency → cytopenias but no blasts, distinct smear (macro/microcytic)

Drug-induced cytopenias: anticonvulsants, sulfa, chemo, chloramphenicol

Step 3 management: Always send a peripheral smear before attributing pancytopenia to viral suppression — the presence of blasts changes everything. In ambiguous cases, repeat CBC and smear in 1–2 weeks if clinically well; refer if cytopenias persist, worsen, or new symptoms develop.

Key distinction: Atypical lymphocytes (mono) are mature reactive cells with abundant cytoplasm; lymphoblasts have scant cytoplasm, fine chromatin, and visible nucleoli. Flow cytometry is definitive.

Secondary Prevention, Discharge Planning, and Long-Term Plan

— PJP prophylaxis: TMP-SMX 3 days/week (or atovaquone, pentamidine, dapsone if intolerant)

— Maintenance chemotherapy as prescribed: 6-MP nightly, weekly methotrexate, monthly vincristine and steroid pulses, intrathecal therapy per schedule

— Antifungal prophylaxis if high risk (history of fungal infection, post-HSCT)

— Acyclovir prophylaxis if HSV/VZV seropositive and on intensive therapy

— Antiemetics PRN, ondansetron-related QT monitoring

— Stool softeners (vincristine-induced constipation)

— Calcium/vitamin D for steroid-related bone effects

— Avoid live vaccines during therapy and for ~6 months after

— Fever ≥38.3°C once or 38.0°C sustained: immediate ER visit, no antipyretic before evaluation

— Neutropenic precautions: avoid sick contacts, raw/undercooked food, gardening, unpasteurized products

— Central line care: daily inspection, dressing changes, signs of infection

— Medication adherence — 6-MP missed doses worsen relapse risk

— When to call: bleeding, severe headache, vision changes, abdominal pain, dyspnea

— Annual inactivated influenza vaccine for patient and household

— Pneumococcal updates

— Hold MMR, varicella, rotavirus, live attenuated influenza during therapy

— Household contacts can receive most vaccines (avoid LAIV; OPV not used in US)

— Re-immunization series 6–12 months after therapy completion

— School reentry plans, 504/IEP for neurocognitive support

— Sun protection (skin malignancy risk, photosensitizing meds)

— Physical activity as tolerated; avoid contact sports if thrombocytopenic

— Transition to survivorship clinic ~2 years post-therapy

— Annual echo, growth and endocrine monitoring, neurocognitive testing, dental care, secondary malignancy screening per Children's Oncology Group LTFU guidelines

Discharge medications after induction:

Family/patient education at discharge:

Vaccinations:

School and lifestyle:

Long-term survivorship:

Board pearl: Live vaccines are contraindicated during ALL therapy and for ~6 months after completion; inactivated influenza is encouraged annually for patient and entire household.

Follow-Up, Monitoring, and Counseling

— Induction: clinic/hospital visits multiple times weekly; daily CBC during nadirs

— Consolidation/Interim maintenance/Delayed intensification: 1–2× weekly clinic visits

— Maintenance: every 4 weeks for vincristine, labs, steroid pulse, intrathecal as scheduled

— CBC with differential weekly during intensive phases, every 2–4 weeks in maintenance

— Comprehensive metabolic panel for hepatic and renal function

— 6-MP dose titration target: ANC 500–1500, platelets >75K — adjust dose to stay in window

— Liver enzymes (6-MP, MTX) — hold if ALT >10× ULN; resume at reduced dose

— Lipase/amylase with asparaginase

— Fibrinogen, AT III during asparaginase phases

— Glucose monitoring during steroid pulses

— Echocardiogram every 1–5 years depending on anthracycline dose and age at exposure

— Annual TSH if neck radiation or cranial radiation

— Growth/pubertal monitoring through adolescence

— Bone density (DEXA) for osteopenia/AVN risk

— Neuropsychological testing at school transitions

— Fertility counseling at puberty and pre-conception

— Skin exams, dental exams

— First 1–2 years: clinic visits every 1–3 months with CBC

— Years 2–5: every 6 months

— Beyond 5 years: annually, transition to survivorship clinic

— No routine imaging unless symptomatic

— Screen for depression, anxiety, PTSD at each survivorship visit (validated tools)

— Sibling and parent support

— School and vocational support

— Sexual health and fertility discussions in adolescence

Active therapy follow-up cadence (varies by phase):

Routine monitoring labs:

Surveillance for late effects (post-therapy):

Off-therapy surveillance for relapse:

Psychosocial counseling:

CCS pearl: Skipping or under-dosing 6-mercaptopurine during maintenance is one of the strongest predictors of late relapse — counsel families that "feeling well" is not a reason to stop; medication diaries and adherence checks at every visit are standard of care.

Ethical, Legal, and Patient Safety Considerations

— Parent/guardian provides legal consent; child provides developmentally appropriate assent (typically age ≥7)

— Adolescents (12+) should have significant voice in treatment decisions and clinical trial enrollment

— Document both parents' consent when feasible, especially for clinical trial enrollment or HSCT

— Mature minor doctrine varies by state but generally limited in life-threatening cancer care

— Refusal of curable pediatric leukemia (>90% survival) is generally not honored — court involvement and Child Protective Services referral are appropriate

— Distinguish from refusal of futile therapy at end of life, where parental autonomy is broader

— Religious objections (e.g., refusal of blood products): work with hospital ethics, sometimes legal authority, and erythropoietin/iron strategies, but emergent transfusion may require court order

— ~90% of US pediatric cancer patients are treated on COG/clinical trial protocols — explain randomization clearly, voluntary participation, right to withdraw

— Suspected child abuse or neglect — including medical neglect (refusal of life-saving therapy) — must be reported

— Bruising patterns in suspected ALL should not be assumed to be abuse, but cytopenia explains pattern; conversely, don't miss true abuse hidden by an ALL diagnosis

— ED handoff: communicate immunosuppression status to triage

— Hospital → home: ensure prescriptions filled, central line supplies, emergency contact, 24/7 oncology hotline number

— Pediatric → adult care transition at ~18–25 years for survivors — structured transition clinics reduce loss to follow-up

— School communication with written plan for fever protocols and absence support

Informed consent and assent:

Refusal of treatment:

Clinical trial enrollment:

Mandatory reporting:

Transitions of care — high-risk safety zones:

Confidentiality in adolescents: balance autonomy with parental involvement; sexual health, contraception, mental health discussions in private

Financial toxicity: discuss insurance navigation, hospital social work, and assistance programs — a recognized health-systems determinant of outcome

Step 3 management: A parent refusing chemotherapy for a child with curable ALL → notify hospital ethics committee, social work, and file a medical neglect report with CPS; this is not optional, even with sympathetic family circumstances.

High-Yield Associations and Rapid-Fire Clinical Facts

Most common pediatric cancer overall: ALL (~25% of childhood cancer)

Peak age: 2–5 years

Highest 5-year survival: >90% in standard-risk pediatric B-ALL

B-ALL CALLA antigen: CD10

Most favorable cytogenetics: hyperdiploidy (>50), t(12;21) ETV6-RUNX1

Worst cytogenetics: hypodiploidy (<44), KMT2A/MLL rearrangements (especially in infants), Ph-like

Ph+ ALL: t(9;22), BCR-ABL1 — add TKI (imatinib/dasatinib) to chemo

T-ALL classic: adolescent male, anterior mediastinal mass, very high WBC

CN VII palsy in a child with cytopenias = CNS leukemia

Painless testicular enlargement on chemo = testicular relapse

Down syndrome: 10–20× increased leukemia risk

Avoid in tumor lysis: IV calcium (unless symptomatic) — precipitates with phosphate

Rasburicase contraindicated in: G6PD deficiency (causes hemolysis, methemoglobinemia)

First step in suspected pediatric leukemia: CBC with differential and peripheral smear

Diagnostic gold standard: bone marrow biopsy with ≥25% lymphoblasts

Strongest prognostic factor after induction: minimal residual disease (MRD) at day 29

Highest TLS risk: T-ALL, Burkitt lymphoma, hyperleukocytosis

Methotrexate antidote: leucovorin; glucarpidase for severe delayed clearance

Cyclophosphamide bladder toxicity prevention: mesna and hydration

6-MP pharmacogenomics: TPMT and NUDT15 — poor metabolizers get profound myelosuppression

Asparaginase complications mnemonic ("A-PAIN"): Anemia/Allergy, Pancreatitis, Ammonia↑/Thrombosis, Insulin↓/Hyperglycemia, Neurologic (CSVT)

Vincristine toxicity: peripheral neuropathy, constipation, SIADH; dose cap 2 mg

Anthracycline toxicity: cardiomyopathy; cumulative dose-dependent

Long-term cancer risk in survivors: secondary AML, brain tumors (post-radiation), thyroid

AYA outcomes: better on pediatric protocols than adult

Live vaccines: contraindicated during therapy and ~6 months post

Board pearl: If the stem mentions a CN VII palsy or testicular asymmetry in a child on or recently off leukemia therapy, the answer is CNS or testicular relapse — order MRI brain/LP or testicular US/biopsy and call oncology.

Board Question Stem Patterns

— Next step: peripheral smear (already done in this stem) → refer urgently to pediatric heme/onc for bone marrow biopsy

— Do not start steroids, do not transfuse aggressively without oncology input

— Tumor lysis syndrome → IV hydration (2× maintenance, no K), rasburicase, treat hyperkalemia, avoid IV calcium unless symptomatic, cardiac monitoring; admit ICU

— T-ALL with mediastinal mass; do not sedate or lay supine; upright imaging, echo for pericardial effusion, urgent oncology, possible empiric steroids

— Febrile neutropenia: blood cultures, CXR, empiric cefepime within 60 minutes, admit

— ITP, not leukemia; observe or steroids/IVIG per bleeding severity. Do not do bone marrow unless atypical features

— CNS leukemia (cranial nerve VII) → MRI, LP with cytology and flow

— Cerebral sinus venous thrombosis → MRI/MRV, anticoagulation, hold asparaginase

— Testicular relapse → biopsy, systemic chemo + bilateral testicular radiation

— Methotrexate hypersensitivity in DS → leucovorin rescue, dose reduction

— Ethics consult + Child Protective Services report for medical neglect; cure rates >90%

"4-year-old with 3 weeks of fatigue, pallor, leg pain refusing to walk, and bruising. Hgb 7, platelets 35K, WBC 22K with circulating blasts."

"7-year-old with high WBC (150K), uric acid 12, K 6.5, phosphorus 8, calcium 7. What's next?"

"Adolescent male with cough, orthopnea, and CXR showing mediastinal widening. WBC 80K with lymphoblasts."

"Child on maintenance presents with fever 39°C, ANC 200."

"5-year-old with isolated platelets of 8K after a viral illness, no organomegaly."

"Child on chemo with new-onset right facial droop."

"Asparaginase day 14, sudden headache and seizures."

"Boy in remission with painless unilateral testicular enlargement."

"Down syndrome infant with severe mucositis and pancytopenia after methotrexate."

"Parents refuse chemotherapy for newly diagnosed standard-risk ALL."

Step 3 management: Pattern-recognize the constellation — cytopenias in ≥2 lineages + organomegaly or bone pain = leukemia until proven otherwise. The wrong-answer trap is empiric steroids, single-lineage workup, or watchful waiting.

One-Line Recap

Pediatric ALL is the most common childhood cancer, classically presenting in a 2–5-year-old with bone pain, pallor, bruising, and cytopenias — diagnosed by ≥25% lymphoblasts on bone marrow biopsy after peripheral smear, with risk-stratified multi-agent chemotherapy producing >90% 5-year survival when initiated urgently and managed for tumor lysis, febrile neutropenia, and CNS disease.

Recognize: cytopenias in ≥2 lineages + hepatosplenomegaly/lymphadenopathy/bone pain/CN VII palsy/mediastinal mass → CBC with manual differential and peripheral smear immediately; refer same day to pediatric oncology and never start empiric steroids before diagnosis

Stabilize: at diagnosis, anticipate tumor lysis (IV hydration, allopurinol or rasburicase, avoid IV calcium and supplemental potassium), febrile neutropenia (empiric cefepime within 60 minutes), mediastinal mass (no supine, no sedation until cytoreduced), and hyperleukocytosis (cytoreduction, avoid PRBC transfusion to high Hgb)

Treat: risk-stratified, ~2–3-year protocol — induction (vincristine, steroid, asparaginase ± anthracycline), consolidation, interim maintenance (high-dose MTX with leucovorin), delayed intensification, maintenance (6-MP, MTX, vincristine, steroids), CNS prophylaxis with intrathecal MTX, TKI added for Ph+ ALL; track MRD at day 29 as the single strongest prognostic marker

Sustain: PJP prophylaxis throughout therapy, no live vaccines until ~6 months post-completion, central line and adherence counseling, fertility preservation in pubertal patients, COG long-term follow-up for cardiomyopathy, neurocognitive effects, endocrine sequelae, and secondary malignancy — and always involve ethics/CPS when curative therapy is refused

Board pearl: When in doubt, get the smear and call oncology — pediatric ALL rewards speed at every decision point.