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Optimizing ALL Treatment
Expert Guidance on Optimizing Treatment Strategies for Acute Lymphoblastic Leukemia

Released: April 16, 2020

Expiration: April 15, 2021

Amir Fathi
Amir Fathi, MD
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Hematopoiesis and Acute Leukemias

Acute leukemias, such as acute myeloid leukemia and ALL, derive from immature precursors that are abnormally arrested in their differentiation and proliferate in the bone marrow. In the case of B‑cell ALL, the arrest occurs at the level of the B‑cell lymphoid blast.1 Classification of acute leukemias has evolved over several decades. First published in 1976, the French, American, and British cooperative group classification categorized ALL as L1, L2, or L3 based on immunophenotype.2,3 Since then, molecular markers and other disease-specific characteristics have been used to establish a more nuanced classification of ALL.

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Epidemiology of ALL in the United States

ALL is an uncommon disease, particularly among adults. According to recent data, approximately 5960 total new cases were reported in the United States in 2019.4 More than half of the adult cases were in patients younger than 20 years of age. Adult patients with ALL have a poorer prognosis than pediatric patients. In 2019, approximately 1500 deaths occurred due to ALL, with a median age at death of 56 years.

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B-Cell ALL: Therapeutic Context

Approximately 75% of adult ALL cases are precursor B‑cell disease, which is the focus of this educational activity.5 The remaining patients have T-cell lineage ALL.

The prognosis in adults with ALL worsens with age at diagnosis. This is partly related to molecular features. The proportion of patients with the presence of the high‑risk Philadelphia chromosome (Ph) increases with age.5 The translocation between chromosomes 9 and 22 results in aberrant BCR-ABL enzyme that leads to proliferation of lymphoid leukemia cells and the phenotype of a Ph-positive B-cell ALL.6 In B‑cell ALL, relapse is associated with poor outcomes, and is quite common with a 3‑year disease‑free survival (DFS) rate ranging from 30% to 50%.7 CR rates with conventional chemotherapy for relapsed/refractory disease range from 31% to 44% at first salvage, declining even further with subsequent salvage attempts.7 These low CR rates impact attempts to make patients eligible for curative modalities such as SCT.

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Risk Factors in Adult ALL

Common risk factors associated with adult ALL include:

  • Older age (> 30 years)
  • Higher WBC count (> 30,000 cells/mm3 in B-cell ALL and > 100,000 cells/mm3 in T-cell ALL)
  • The presence of the Ph chromosome with BCR-ABL translocation
  • The presence of Ph‑like lesions
  • The presence of other chromosomal and molecular abnormalities, including t(4;11), 11q23, MLL rearrangement, and hypodiploidy (≤ 44 chromosomes)
  • Central nervous system involvement, as detected by lumbar puncture or imaging
  • Measurable residual disease (MRD) positivity (> 10-4 or 0.01%) after induction chemotherapy

ALL Cure Rates Decrease With Age

As mentioned above, the prognosis of patients with ALL worsens with increasing age. Generally speaking, pediatric and young adult patients tend to have good long‑term outcomes.4 In patients aged 30 years or older at ALL diagnosis, the prognosis is worse, and incrementally so with advancing age at diagnosis.8 Other studies have also demonstrated a steady decline in survival and worsening prognosis in older adult patients.9

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Poor Prognosis of Relapsed ALL in Adults

Long‑term outcomes among adults with relapsed/refractory ALL are particularly poor. A large British study of more than 600 patients with ALL demonstrated a 5-year OS rate of 7% after first relapse that worsens with increasing age.10 Another study of more than 400 patients with ALL showed a median OS of 6.3 months following the first relapse with a 5-year OS rate of 8%.11 These findings confirm that once adult patients with ALL relapse, they have very poor survival outcomes.

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Ph-Like Lesions in ALL

Ph-like ALL is distinct from Ph-positive disease, which is associated with the presence of Ph with t(9;22). Ph-like cases refer to those with various molecular lesions leading to similar gene expression profiles to those of Ph-positive ALL but without the presence of the Ph.12

Ph-like B‑cell ALL, like Ph-positive disease, has worse event-free survival (EFS) and OS compared with other cases of B-cell ALL. Among patients who have Ph‑like lesions, those with translocations involving the CRLF2 gene appear to have a particularly poor prognosis. Patients with Ph-like ALL generally require a more aggressive induction regimen as well as consolidation therapy incorporating SCT.

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