Pediatric ALL with Induction Failure Is Highly Heterogeneous with Varying Outcomes

Get Permission

While failure of remission-induction therapy is rare in children and adolescents with acute lymphoblastic leukemia (ALL), when it does occur it is highly adverse and heterogeneous, according to a study in The New England Journal of Medicine. “Patients who have T-cell leukemia appear to have a better outcome with allogeneic stem-cell transplantation than with chemotherapy, whereas patients who have precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy,” the authors reported.

“We identified induction failure, defined by the persistence of leukemic blasts in blood, bone marrow, or any extramedullary site after 4 to 6 weeks of remission-induction therapy, in 1,041 of 44,017 patients (2.4%) 0 to 18 years of age with newly diagnosed ALL who were treated by a total of 14 cooperative study groups between 1985 and 2000,” they stated.

“Patients with induction failure frequently presented with high-risk features, including older age, high leukocyte count, leukemia with a T-cell phenotype, the Philadelphia chromosome, and 11q23 rearrangement,” they reported. At a median follow-up period of 8.3 years, the 10-year estimated survival was 32% ± 1%.

Factors associated with a particularly poor outcome were an age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction therapy. Allogeneic stem-cell transplantation from matched, related donors was associated with improved outcomes in T-cell leukemia.

Factors associated with a favorable outcome in patients with precursor B-cell leukemia were high hyperdiploidy (a modal chromosome number > 50) and an age of 1 to 5 years. Children younger than 6 years of age with precursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72% ± 5% when treated with chemotherapy only.

Differences among Study Groups

“Treatment strategies for patients with induction failure differed among the study groups,” the authors noted. “Seven study groups assigned these patients to the highest-risk treatment group, whereas other study groups enrolled such patients in an alternative trial of leukemia therapy or treated them with individualized therapy. Although the indications for allogeneic transplantation during the first period of complete remission varied among the study groups, induction failure was a consensus indication for allogeneic transplantation. HLA-matched, related-donor transplantation was generally the preferred method among various alternatives to chemotherapy alone,” the study authors reported.

“A key finding is that the prognostic value of various clinical and biologic features of ALL at diagnosis also holds true within the microcosm of ALL induction failure,” an editorial accompanying the article noted. “These data also highlight the complex interrelationship between disease biology and early treatment response—that is, inferior initial responses to therapy portend different outcomes within unique biologic subgroups.” The superiority of chemotherapy to stem-cell transplantation in children younger than 6 years of age with precursor B-cell ALL (without MLL rearrangement) “is striking and may substantially affect current practice, since stem-cell transplantation has generally been accepted as the preferred treatment for all cases of induction failure,” according to the editorial.

“The general insights obtained in this study apply not just to induction failure, but to ALL overall,” the editorial continued. “From this remarkable collaborative effort we learn that induction failure is not a single entity with a uniform prognosis but rather exhibits biologic and prognostic heterogeneity. It is possible that sophisticated risk stratification and risk-directed treatment may lead to improved outcomes.” ■

Schrappe M, et al: N Engl J Med 366:1371-1381, 2012.

Rabin KR: N Engl J Med 366:1445-1446, 2012.