What are the factors associated with a worse prognosis in B-cell acute lymphoblastic leukemia (B-ALL)?

Factors Associated with Worse Prognosis in B-cell Acute Lymphoblastic Leukemia

Two key factors with worse prognosis in B-ALL are: (1) hypodiploidy (particularly low hypodiploidy with 30-39 chromosomes or near haploidy with <30 chromosomes), and (2) KMT2A (MLL) gene rearrangements, especially in infants. 1

Hypodiploidy

Hypodiploidy represents one of the most adverse cytogenetic features in B-ALL, occurring in 1-2% of pediatric patients. 1

• Low hypodiploidy (30-39 chromosomes) and near haploidy (<30 chromosomes) are well-recognized prognostic biomarkers of high-risk disease at all ages 1
• Low hypodiploidy is associated with a high frequency of TP53 alterations, which are germline in approximately 50% of cases, warranting consideration for germline testing 1
• Patients with hypodiploidy (<44 chromosomes) are classified as having high-risk or very-high-risk disease 1

KMT2A (MLL) Gene Rearrangements

KMT2A rearrangements are associated with poor outcomes, particularly in infants where they occur in 70-80% of cases. 1

• These chromosomal rearrangements occur in approximately 5% of pediatric ALL cases overall, but have dramatically higher incidence in infants 1
• The t(4;11) translocation is among the most common KMT2A rearrangements and carries particularly poor prognosis 1
• Patients younger than age 1 with KMT2A gene rearrangement are classified as high-risk or very-high-risk disease 1
• In infant ALL with KMT2A rearrangements, the 5-year event-free survival remains approximately 56-66% even with intensive chemotherapy 1, 2

Additional High-Risk Cytogenetic and Molecular Features

BCR-ABL1 (Philadelphia chromosome-positive) ALL is associated with poor prognosis, occurring in 2% of childhood ALL but 25% of adult ALL. 1

• The frequency of Ph-positive ALL increases with age, and younger children (1-9 years) with Ph-positive ALL have better prognosis than adolescents 1
• Patients with t(9;22) chromosomal translocation and/or presence of BCR-ABL1 fusion gene are classified as high-risk or very-high-risk 1

The t(17;19)/TCF3-HLF fusion defines a rare subtype (<1% of pediatric ALL) associated with poor outcomes. 1

BCR-ABL1-like (Ph-like) ALL is a subgroup associated with unfavorable prognosis occurring in approximately 15% of pediatric patients. 1

• The 5-year disease-free survival in the BCR-ABL1-like ALL group is estimated at 60% in pediatric patients 1
• In adult patients with BCR-ABL1-like ALL, the 5-year event-free survival is significantly lower at 22.5% compared with 49.3% in non-BCR-ABL1-like ALL 1

IKZF1 (Ikaros gene) mutations are seen in approximately 15-20% of pediatric B-ALL and are associated with poor prognosis and greater incidence of relapse. 1

• IKZF1 mutations occur at higher frequency (>75%) in patients who are also BCR-ABL1 positive 1
• IKZF1 deletions with co-occurring deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion confer poor outcomes 1

iAMP21 (intrachromosomal amplification of chromosome 21) occurs in approximately 2% of children with ALL and is associated with adverse prognosis when treated with low-intensity regimens. 1

Clinical Risk Factors

Initial white blood cell count >300 × 10⁹/L is strongly related to poor outcome in B-ALL patients with KMT2A rearrangements. 3

Failure to achieve remission with induction therapy is a defining characteristic of high-risk or very-high-risk disease. 1

Positive minimal residual disease (MRD) after induction is strongly related to poor outcome and represents the most important prognostic factor. 3, 2

• MRD ≥0.01% at the end of early consolidation is a significant factor for poor prognosis in multivariable analysis 2
• Positive FCM-MRD levels are strongly related to poor outcomes 3