Allogeneic stem-cell transplantation is not always the best option when pediatric acute lymphoblastic leukemia fails to respond adequately to induction therapy, according to a report in the April 12 issue of the New England Journal of Medicine.

Children who have the precursor B-cell subtype and no other adverse features do better when treated with chemotherapy, investigators report. Those with T-cell leukemia appear to have better outcomes with allogeneic stem-cell transplantation, a common treatment of choice after induction failure.

Eighty percent of children with pediatric acute lymphoblastic leukemia (ALL) can be cured with standard treatments. The small proportion of children in the very-high-risk group that does not respond to induction therapy is much more heterogeneous than clinicians may realize, according to Dr. Martin Schrappe of Schleswig-Holstein University Medical Center, Christian-Albrechts University, Kiel (Germany) and his associates.

The authors pooled the findings of multiple clinical trials performed by 14 cooperative study groups in North America, Europe, and Asia between 1985 and 2000. Based on this observational analysis, ALL with induction failure was found to be a highly varied entity, with different clinical and biologic traits and a wide range of prognoses.

The study assessed outcomes in 44,017 children and adolescents (aged 0-18 years) with newly diagnosed ALL who were enrolled in clinical trials during that interval and were followed for a median of 8.3 years (range, 1.5-22.1 years). A total of 1,041 (2.4%) failed induction therapy, showing persistent leukemic blasts in the bone marrow or at extramedullary sites.

Overall 10-year survival was 32% but varied greatly across the cohort, from 4% to 73%, depending on biological and clinical factors.

Patients with induction failure were much more likely than ALL patients as a whole to have conventional adverse prognostic factors such as a high leukocyte count, older age at disease onset, the BCR-ABL1 gene, and T-cell phenotypes – and these factors conferred an even worse prognosis in this already high-risk population.

"Indeed, the clinical and biologic characteristics of the patients in our study and the course of the disease were similar to those in patients with relapse during receipt of therapy, another group of patients with a highly unfavorable prognosis," the researchers said.

Among patients who eventually achieved a late remission, 10-year survival was significantly higher (48%) than among those who never achieved a remission (14%).

A total of 198 patients underwent hematopoietic stem-cell transplantation and 427 received chemotherapy only. The 10-year survival was 43% with transplantation and 41% without it.

Surprisingly, allogeneic transplantation was shown to be of no benefit in patients younger than 6 years who had precursor B-cell ALL with induction failure and no high-risk features, compared with chemotherapy alone. This finding has "considerable clinical implications, since transplantation is generally considered to be the standard of care for such patients," Dr. Schrappe and his colleagues said (N. Engl. J. Med. 2012;366:1371-81).

In patients aged 6 years and older who had precursor B-cell ALL, a transplant from a matched, related donor appeared to improve outcome, while other types of allogeneic transplants actually worsened outcomes. This was due in part to a high number of transplantation-related deaths in the latter group.

In contrast, allogeneic transplantation appeared to improve outcomes in the subgroup of patients who had T-cell ALL and failed induction therapy.

Patients with high hyperdiploidy (more than 50 chromosomes) showed an excellent outcome, with a 10-year survival rate of 71%. This favorable outcome "may be due to the increased sensitivity of the blast cells to methotrexate and mercaptopurine, drugs that are generally not used during remission induction but are used at high doses after remission," the investigators said.

Patients who carried the genetic aberration ETV6-RUNX1 also had a high 10-year survival of 73%, which is more than double the survival rate in the cohort as a whole.

Survival was lower among patients who had M3 marrow after induction therapy, compared with those who had M1 marrow and extramedullary disease or M2 marrow. Subgroups with the worst outcomes included patients aged 6 years or older who had M3 marrow (10-year survival, 22%) and those of any age who had T-cell ALL and M3 marrow (10-year survival, 19%).

Among infants who had precursor B-cell ALL and did not have a rearrangement of the MLL gene or fusion of the BCR-ABL1 gene, outcomes were similar to those in children aged 1-5 years (10-year survivals of 65% and 63%, respectively). In contrast, infants who had a rearrangement of the MLL gene fared very poorly (10-year survival, 4%) compared with older children who had the same genetic abnormality (10-year survival, 26%).

Numerous hospitals, charities, and government agencies supported this study. Dr. Schrappe reported ties to Medoc and EUSA Pharm; his associates reported ties to numerous industry sources.

Consider Chemotherapy after Induction Failure for Childhood Leukemia