Types

The World Health Organization (WHO) classification system is the most commonly used method to distinguish acute lymphoblastic leukemia (ALL) subtypes.¹

Classification¹

Based on the type of white blood cell (lymphocyte) affected, two main subtypes can be found:

B-cell ALL (B-ALL), the most common type (80% of cases)

• Most B-ALL stems from abnormal immature (pre) B cells.
• Some B-ALL develops from malignant mature B cells. You may also hear it called Burkitt-type ALL, as it is similar to another type of cancer called Burkitt lymphoma.²

T-cell ALL (T-ALL; 20% of cases)

More frequent in young adults and in men.

Further classification²

Leukemia subtypes can be further categorized into around 25 different subtypes according to the genetic abnormalities present. These genetic subtypes are very important for patient management, helping doctors to confirm a diagnosis and select the optimal treatment pathway; some genetic subtypes indicate that the disease will respond to a specific drug while others can indicate the aggressiveness of the leukemia. Doctors will use the genetic subtype in combination with other factors, like age and response to treatment, to determine the level of chemotherapy required by each patient.

The frequency of genetic subtypes varies by patient age and time of diagnosis.

It is important to remember that the genetic abnormalities discussed in this section only affect leukemic cells and do not affect non-cancer cells. They are not inherited from your parents and are not passed on to your children.

B-ALL¹

Philadelphia-positive ALL

The most common genetic abnormality in adult ALL is the formation of the Philadelphia (Ph) chromosome; this is caused by the exchange of genetic material between Chromosomes 9 and 22 in leukemic cells, resulting in the creation of the BCR::ABL1 fusion gene. The presence of this fusion gene confers a sensitivity to a class of drug called tyrosine kinase inhibitors. Ph-positive ALL occurs in 20–30% of adults, but only 2% of children. You can read more about this and other therapies on the treatment page.

Philadelphia-like ALL

Characterized by a similar gene expression profile to Ph-positive ALL but lacks the BCR::ABL1 gene fusion. Although Ph-like ALL can occur at any age, it most frequently occurs in adolescents and adults. This subtype comprises two subgroups: ABL1 class fusions and JAK-STAT activated. The presence of an ABL-class fusion, but not a JAK-STAT abnormality, confers sensitivity to a class of drug called tyrosine kinase inhibitors.

ETV6::RUNX1 fusion or t(12;21)(p13;q21) ALL

This is a common genetic abnormality in children with ALL, occurring in 25–30% of cases; however, it is very rare in adults. Children with ETV6::RUNX1-positive ALL generally have good outcomes and are usually treated with standard chemotherapy.

High hyperpdiploid ALL

This is the most common genetic abnormality in children with ALL, occurring in 30–35% of cases andonly occurring in around 10% of adults. It is characterized by the multiple gain of whole chromosomes. Most children with high hyperdiploid ALL have a very good response to chemotherapy.

KMT2A or MLL gene fusion ALL

Abnormalities involving the KMT2A gene can occur at any age and are usually associated with aggressive disease. Around 80% of infant patients (aged <1 year) will have this genetic subtype. It is rare in children (2–3%) but starts to increase in frequency with age—accounting for around 10% of adults with ALL.

Hypodiploidy ALL

This genetic subtype is characterized by multiple chromosome losses and associated with aggressive disease. There are two subgroups: near haploidy and low hypodiploidy. Both subgroups are rare in children, accounting for 1–2% of cases. Near haploid ALL is extremely rare in adults but low hypodiploidy occurs in around 10%, especially in older patients (aged >50 years).

iAMP21 ALL

This genetic subtype involves a very complex rearrangement of Chromosome 21 and gives rise to an aggressive form of the disease. It most frequently occurs in older children (aged 8–14 years) and is rare in other age groups.

ABL-class gene fusion ALL

This genetic subtype comprises a series of gene fusions involving one of the following genes: ABL1, ABL2, CSF1R, and PDGFRB. Similar to patients with the BCR::ABL1 fusion gene, these patients are usually sensitive to tyrosine kinase inhibitors, with many patients treated with imatinib or dasatinib, alongside standard chemotherapy. This genetic subtype is quite rare, accounting for 2–3% of cases.

Other B-ALL subtypes include t(5;14)(q31.1;q32.3)/IGH::IL3, t(1;19)(q23.3;p13.3)/TCF3::PBX1,TCF3::HLF fusion, MYC rearrangement, DUX4 rearrangement, MEF2D rearrangement, ZNF384(362) rearrangement, NUTM1 rearrangement, CDX2/UBTF, IKZF1 N159Y mutation, PAX5 P80 Rmutation, ETV6::RUNX1-like, PAX5 alteration, ZEB2 (p.H1038R) mutation/IGH::CEBPE, ZNF384-like, and KMT2A-like.

T-ALL

T-cell ALL can be further classified according to both immunophenotype and genetics. Whilst many subtypes have been described in the research literature, the clinical relevance and prognostic value are not well understood. Further research is needed before these subtypes are widely and consistently used in the clinical setting.

This list of genetic subtypes is not exhaustive, we have focused on the most common subtypes used by doctors to make treatment decisions. The official classification of ALL can be found in The WHO classification.¹