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    Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Postinduction Treatment for Childhood ALL

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    Very high-risk ALL

    Approximately 10% to 20% of patients with ALL are classified as very high risk, including the following:[17,28]

    • Infants.
    • Patients with adverse cytogenetic abnormalities, including t(9;22), MLL gene rearrangements, and low hypodiploidy (<44 chromosomes).
    • Patients who achieve complete remission but have a slow early response to initial therapy, including those with a high absolute blast count after a 7-day steroid prophase, and patients with high minimal residual disease (MRD) levels at the end of induction (week 4) or later time points (e.g., week 12).
    • Patients who have morphologically persistent disease after the first 4 weeks of therapy (induction failure), even if they later achieve complete remission.

    COG also considers patients who are aged 13 years or older to be very high risk, although this age criterion is not utilized by other groups.

    Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase (usually in addition to the typical BFM-backbone intensification phases). These additional cycles often include agents not typically used in frontline ALL regimens for standard-risk and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide.[17] However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient subset.[17,29]

    On some clinical trials, very high-risk patients have also been considered candidates for allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, [29,30,31] although it is not clear whether outcomes are better with transplantation.

    Evidence (allogeneic HSCT in first remission for very high-risk patients):

    1. In a European cooperative group study, very high-risk patients (defined as one of the following: morphologically persistent disease after a four-drug induction, t(9;22) or t(4;11), or poor response to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells [WBC] >100,000/μL) were assigned to receive either an allogeneic HSCT in first remission (based on the availability of a human lymphocyte antigen-matched related donor) or intensive chemotherapy.[29]
      • Using an intent-to-treat analysis, patients assigned to allogeneic HSCT (on the basis of donor availability) had a superior 5-year disease-free survival (DFS) compared with patients assigned to intensive chemotherapy (57% ± 7% for transplant versus 41% ± 3% for chemotherapy, P = .02)
      • There was no significant difference in overall survival (OS) (56% ± 6% for transplant versus 50% ± 3% for chemotherapy, P = .12).
      • For patients with T- cell ALL and a poor response to prednisone prophase, both DFS and OS rates were significantly better with allogeneic HSCT.[30]
    2. In another study of very high-risk patients that included children with extremely high presenting leukocyte counts and those with adverse cytogenetic abnormalities and/or initial induction failure (M2 marrow [between 5% and 25% blasts]), allogeneic HSCT in first remission was not associated with either a DFS or OS advantage.[31]
    3. In a large retrospective series of patients with initial induction failure, the 10-year OS for patients with persistent leukemia was 32%.[32]
      • A trend for superior outcome with allogeneic HSCT, compared with chemotherapy alone, was observed in patients with T-cell phenotype (any age) and with B-precursor ALL who were older than 6 years.
      • Patients with B-precursor ALL who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (MLL translocation, BCR-ABL) had a relatively favorable prognosis, without any advantage in outcome with the utilization of HSCT compared with chemotherapy alone.
    4. In a Dutch and Australian trial of 111 children with high-risk features or high MRD, patients received three novel intensive chemotherapy agents followed by allogeneic transplantation. Thirty of these patients were high risk by MRD and had a 5-year EFS of 64%.[33]
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