What is the approach to diagnosis and treatment in pediatric patients presenting with blast cells, potentially indicating a hematological malignancy such as acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML)?

Approach to Blast Cells in Pediatric Patients

Diagnostic Criteria

The diagnosis of acute lymphoblastic leukemia (ALL) in pediatric patients requires ≥20% bone marrow lymphoblasts on hematopathology review, though ≥25% is often used in treatment protocols to define leukemia. 1 Presentations with <20% marrow blasts should avoid an ALL diagnosis, as there is no compelling evidence that delaying treatment at these low blast counts adversely affects outcomes. 1

Alternative Diagnostic Approaches

• When bone marrow aspirate is precluded by clinical circumstances (hyperleukocytosis ≥100,000 leukocytes/μL or mediastinal mass), peripheral blood may substitute if there are ≥1,000 circulating lymphoblasts/μL or ≥20% lymphoblasts. 1

• For lymphoblastic lymphoma (LL), the disease is restricted to mass lesions (nodal or extranodal) with <20% marrow lymphoblasts, but is treated identically to ALL with ALL-directed regimens. 1

Essential Diagnostic Workup

Morphologic Assessment

• Wright-Giemsa–stained bone marrow aspirate smears 1
• Hematoxylin and eosin–stained core biopsy and clot sections 1
• Physical examination focusing on spleen size (cm below costal margin), liver size, and extramedullary manifestations 1

Immunophenotyping

Flow cytometric classification is mandatory to distinguish B-ALL (80% of pediatric cases) from T-ALL (10-15% of cases). 1

• B-ALL markers: CD19, CD22, CD79a, commonly CD10 2, 3
• T-ALL markers: Cytoplasmic CD3 or surface CD3, variable CD2/CD5/CD7, CD1a, CD99 1
• Notable findings: CD10 negativity correlates with KMT2A rearrangement; early T-cell precursor (ETP) T-ALL lacks CD5, CD8, CD1a expression 1

Genetic Characterization

Optimal risk stratification requires comprehensive genetic testing of marrow or peripheral blood lymphoblasts: 1

• Karyotyping of G-banded metaphase chromosomes (minimum 15 metaphases analyzed) 1
• FISH testing for major recurrent abnormalities including hyperdiploidy detection (chromosomes 4,10,17), t(12;21), BCR::ABL1, KMT2A rearrangements, iAMP21 1
• RT-PCR testing for BCR::ABL1 in B-cell ALL 1
• Baseline clonal characterization by flow cytometry or molecular assay (Ig/TCR gene rearrangements) to facilitate minimal residual disease (MRD) monitoring 1

Critical Differential: CML Blast Phase vs. Ph+ ALL

In pediatric patients with lymphoid blasts and BCR::ABL1, distinguishing CML blast phase (CML-BP) from Ph+ ALL is essential as treatment differs. 1

Features Suggesting CML-BP Rather Than Ph+ ALL:

• Increased basophils or eosinophils 1
• Leukocytosis with left-shifted myeloid maturation 1
• High leukocyte counts at presentation 1
• p210BCR-ABL1 fusion protein (though present in 10-20% of Ph+ ALL) 1
• BCR::ABL1 detected in neutrophils by interphase FISH is confirmatory for CML-BP 1

Additional CML-BP Diagnostics:

• BCR::ABL1 tyrosine kinase domain mutation analysis by NGS (mutations present in 75% of de novo CML-BP, 62% of secondary CML-BP) 1
• Bone marrow trephine biopsy to assess focal "nests of blasts" and fibrosis 1
• Cerebrospinal fluid cytology 1

Risk Stratification for ALL

Unfavorable Risk Features:

• Hypodiploidy (<44 chromosomes) 4, 2
• t(9;22)(q34.1;q11.2), BCR::ABL1 (Philadelphia chromosome) 4, 2
• KMT2A (MLL) rearrangements 4, 2
• Intrachromosomal amplification of chromosome 21 (iAMP21) 4, 2
• t(17;19)(q22;p13.3) [TCF3::HLF] 1

Favorable Risk Features:

• Hyperdiploidy (51-67 chromosomes) 1
• t(12;21) [ETV6::RUNX1] 1

Treatment Approach

All pediatric patients with blast cells suspicious for acute leukemia must be treated at specialized cancer centers with expertise in ALL/AML management. 1, 3

Immediate Management:

• Tumor lysis syndrome prophylaxis: Aggressive hydration and rasburicase before initiating steroids or chemotherapy 4, 2
• Hyperleukocytosis management (if ≥100,000 leukocytes/μL): Leukapheresis for symptomatic patients, early chemotherapy initiation 4
• Premedication protocol: Acetaminophen, H1-blocker (diphenhydramine), H2-blocker (famotidine) 30-60 minutes prior to chemotherapy 5

Treatment Selection:

• B-ALL and T-ALL: Multi-agent chemotherapy regimens lasting 2-3 years with CNS prophylaxis 3
• Philadelphia chromosome-positive (Ph+) ALL: Tyrosine kinase inhibitors combined with chemotherapy 2
• CML blast phase: TKIs combined with acute leukemia-type chemotherapy, followed by allogeneic stem cell transplantation after achieving remission 1, 4
• Relapsed/refractory B-ALL: Clinical trials preferred; tisagenlecleucel (CAR T-cell therapy) or inotuzumab ozogamicin 2

Monitoring Requirements:

• Weekly monitoring with bilirubin, transaminases, glucose, and clinical examinations until recovery from each therapy cycle 5
• MRD assessment using baseline clonal markers established at diagnosis 1
• Long-term surveillance: Echocardiogram for anthracycline cardiotoxicity, neuropsychological testing, endocrine function, secondary malignancy screening 4, 2

Common Pitfalls

• Avoid diagnosing ALL with <20% marrow blasts unless there is clear evidence of lymphoblastic lymphoma with mass lesions 1
• Do not rely on morphology alone to distinguish myeloid from lymphoid lineage; comprehensive flow cytometry is essential 3
• In mixed phenotype presentations, myeloid-associated antigens (CD13, CD33) may be expressed in ALL and do not exclude ALL diagnosis or confer adverse prognosis 1
• For CML-BP vs. Ph+ ALL, perform parallel monitoring of BCR::ABL1 and IgH/TCR or flow cytometry markers; divergence between clonal markers and BCR::ABL1 levels should prompt diagnostic reevaluation 1