BCR::ABL1-Positive (Philadelphia Chromosome–Positive) ALL

BCR::ABL1-positive (Philadelphia chromosome–positive [Ph+]) ALL is seen in about 3% of pediatric ALL cases, increases in adolescence, and is seen in 15% to 25% of adults. In the past, this subtype of ALL has been recognized as extremely difficult to treat, and patients had a poor outcome. In 2000, an international pediatric leukemia group reported a 7-year EFS rate of 25%, with an OS rate of 36%.[86] In 2010, the same group reported a 7-year EFS rate of 31% and an OS rate of 44% in patients with BCR::ABL1 ALL treated without tyrosine kinase inhibitors (TKIs).[87] Treatment of this subgroup has evolved, from an initial emphasis on aggressive chemotherapy, to allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission (CR) as the standard of care, and currently to combination therapy using chemotherapy plus a TKI, with only a small number of patients allocated to allogeneic HSCT in first CR.

For patients with ALL and BCR::ABL1 gene fusions, MRD detection based on flow cytometry or detection of immunoglobulin/T-cell receptor (IG/TCR) rearrangements by either polymerase chain reaction (PCR) or next-generation sequencing (NGS) provides more reliable prognostication than methods based on quantification of BCR::ABL1 fusion transcripts or DNA.[88-90] In some cases, BCR::ABL1 fusion transcripts or DNA may persist in the absence of detectable MRD by flow cytometry or assays of IG/TCR rearrangements. This pattern is characteristic of BCR::ABL1–positive ALL with multilineage involvement. The multilineage subtype is distinguished from the more common subtype, BCR::ABL1–positive ALL with lymphoid-only involvement, in that the BCR::ABL1 fusion can be found in normal non-ALL B cells, T cells, and myeloid cells, as opposed to just lymphoblasts.[91,92] The persistence of BCR::ABL1 fusion DNA or RNA in BCR::ABL1–positive ALL with multilineage involvement likely represents evidence of a residual preleukemic clone and not leukemia cells. Therefore, the term MRD is a misnomer. Based on the limited numbers of patients studied to date, prognosis appears similar in both adults and children with lymphoid-only versus multilineage involvement BCR::ABL1–positive ALL.[88,89] In addition, it does not appear that persistence of BCR::ABL1 PCR positivity (in the absence of detectable MRD by other assays) has prognostic implication. Thus, for BCR::ABL1–positive ALL, flow cytometry and/or IG/TCR PCR or NGS assays are more reliable methods than BCR::ABL1 PCR to assess MRD for risk stratification and treatment decisions. For more information, see the Cytogenetics/Genomics of Childhood ALL section.