ALL is a heterogeneous hematologic cancer that involves uncontrolled growth and subsequent build-up of immature lymphocytes in the bone marrow, peripheral blood, and other organs. Compared to other cancer types, ALL is relatively common among children in the United States with more than 50% of cases reported in individuals younger than 20 years and about one-fourth are reported in individuals older than 45 years. ALL is the most common childhood leukemia accounting for about 75% to 80% of all acute leukemias among children. The median age at diagnosis for ALL is 15 years.
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Prognostic Risk Stratification in ALL
Prognostic risk stratification refers to the classification of patients with ALL into different risk-groups based on various known/validated prognostic factors. Identified prognostic factors for ALL include Patient’s age, WBC count at the time of diagnosis, immunophenotypic or cytogenetic subtype, CNS and other organ involvement, and response to induction therapy. Based on the immunophenotypes, the ALL is broadly categorized into following types: early pre-B-cell ALL, pre-B-cell ALL, mature B-cell ALL, and T-cell ALL. T-cell ALL occurs in about 25% of the cases and is generally associated with poor disease prognosis.
Historically, patient’s age and WBC count at diagnosis have been regarded as strong independent prognostic factors for ALL. Considering the prevalence of ALL in children and adults, separate risk stratification has been proposed for the following 2 age-groups: Adolescent and Young Adults (AYA) patients (>/=15 to <39 years of age) and Adult patients (>/=40 to <60 years of age). Young patients generally have a better disease prognosis and better response to treatment compared to the old-age individuals. The exception to this criterion is patients younger than 1 year of age who are generally considered to be at very high risk.
Presence of Philadelphia chromosome (Ph) is another important independent prognostic factor that has been known since long as a predictor of poor disease prognosis. Many clinical research studies have reported that individuals with Ph+ ALL have significantly poor disease prognosis compared those with Ph-negative ALL. Based on these findings, patients will ALL are mainly divided into the following four risk groups:
|Ph+ ALL in Adult patients||Patients with age >/=40 years and who are positive for Philadelphia chromosomal abnormality|
|Ph+ ALL in AYA patients||Patients with age 15 to 39 years and are positive for Philadelphia chromosomal abnormality|
|Ph- ALL in Adult patients||Patients with age >/=40 years and who are positive for Philadelphia chromosomal abnormality|
|Ph- ALL in AYA patients||Patients with age 15 to 39 years and are negative for Philadelphia chromosomal abnormality|
With the progress in understanding of the disease and advancement in genetic diagnostic techniques, immunophenotypic/cytogenetic characterization has become an important parameter risk stratification. AYA patients and adult patients (<65 years of age or without any significant comorbidities) with Ph-negative ALL can be further considered high-risk if they have any one of the following parameters: 1) positive minimal residual disease (MRD), 2) an elevated WBC count (>/=30* 10^9/L for B-cell ALL; >/=100*10^9/L for T-cell ALL), or presence of any of the following poor-risk cytogenetic: hypodiploidy (<44 chromosomes); BCR-ABL1-like or Ph-like ALL; intrachromosomal amplification of chromosome 21 (iAMP21). The absence of all high-risk factors is considered standard risk. Presence of the following cytogenetic abnormalities (favorable prognostic factors) has been linked to better prognosis: hyperdiploidy (presence of 51-65 chromosomes); the t(12;21) chromosomal translocation (ETV6-RUNX1 subtype); and simultaneous trisomies of chromosomes 4, 10, and 17.
Following table summarizes various positive (favorable) and negative (unfavorable) prognostic factors for ALL and respective diagnostic tests for their determination:
|Favorable Prognostic factors||Unfavorable Prognostic factors||Diagnostic Test for Identification|
|Younger age (except less than 1 year)||Older age||NA|
|B-cell lineage||T-cell lineage||Immunophenotypic analysis or flow cytometry|
|Ph-negativity or BCR-ABL1-negativity||Ph-positivity or BCR-ABL1-positivity||fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR)|
|Normal WBC count||Elevated WBC count||Complete blood cell count (CBC)|
|simultaneous trisomies of chromosomes 4, 10, and 17||iAMP21|
|ETV6-RUNX1 subtype||BCR-ABL1–like ALL||Cytogenetic analysis or next-generation sequencing (NGS)|
|translocations in the KMT2A gene (MLL translocation)|
|mutations in the Ikaros gene (IKZF1)|
|Complex karyotype (5 or more chromosomal abnormalities)|
|CNS involvement||Lumbar puncture or Imaging technique: MRI|
|Response to induction therapy||MRD||PCR or RT-PCR|
With the availability of more data from different research studies, cytogenetics is now considered more valuable in predicting disease prognosis, while prognostic factors such as WBC count have lost its independent prognostic significance.