Induction failure is rare, occurring in only 2 to 3% of all patients, but it constitutes one of the most unfavorable outcomes in pediatric ALL. In our large retrospective series of patients with induction failure, we observed great clinical and biologic heterogeneity. Among these patients, as compared with an unselected population of children and adolescents with ALL, the conventional adverse prognostic factors such as high leukocyte count, older age, positivity for t(9;22)(BCR-ABL1
), and T-cell phenotype were more prevalent and conferred an even worse prognosis.6,12,18,35-39
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.40-44
The patient subgroup with the best outcomes comprised patients with precursor B-cell ALL and either an age of less than 6 years or high hyperdiploidy. Together, these factors accounted for approximately 25% of all patients with induction failure and were associated with a 10-year survival rate above 50%. Although the favorable prognosis of high hyperdiploidy is well recognized in unselected patients with precursor B-cell ALL,18,45-47
this association has not been reported in patients with induction failure. Why did patients with high hyperdiploidy have a relatively favorable prognosis despite the failure of remission-induction therapy? It is unlikely that many of these patients were misdiagnosed as having induction failure, because hematogones (benign immature B-cell precursors that may be mistaken for leukemic cells) should not preferentially occur in patients with high hyperdiploidy. The relatively favorable outcome in patients with high hyperdiploidy may be due to the increased sensitivity of the blast cells to methotrexate and mercaptopurine,45,48
drugs that are generally not used during remission induction but are used at high doses after remission.
The time at which the response was evaluated in these patients also did not have a prognostic effect, most likely because the number of patients in each study group was too small to show a statistical difference (Tables 1 and 2 in the Supplementary Appendix
). The Dana–Farber Cancer Institute Consortium has reported that outcomes are not adversely affected by a hypocellular bone marrow at the end of induction therapy or by a delay in reaching complete remission (defined as normal cellular M1 marrow, a neutrophil count of >1×109
per liter, a platelet count of >100×109
per liter, and no extramedullary disease).21
Our current analysis showed that among patients with induction failure, the patients with an M3 marrow, as compared with those with an M1 or M2 marrow, had a poor outcome. The degree of leukemic involvement in bone marrow at the end of the induction phase was inversely correlated with the rate of subsequent complete remission (81% in patients with M1 or M2 marrow but only 61% in those with M3 marrow) and with 10-year survival rates (41±3% with M1 or M2 marrow vs. 26±3% with M3 marrow). Patients who did not have a complete remission after a brief course of additional therapy, as specified in the treatment protocol, (i.e., 25% of all patients with initial induction failure) had an extremely poor prognosis ().
The extremely poor prognosis of patients with t(9;22)(BCR-ABL1
) and induction failure in the era before imatinib therapy was available has been described.21,23,25,49
A recent study34
showed improved early outcomes with intensive chemotherapy and imatinib treatment in patients with ALL who were positive for t(9;22)(BCR-ABL1
); the nine patients who were positive for t(9;22)(BCR-ABL1
) and had induction failure had a rather favorable outcome. However, the long-term efficacy of this treatment approach as compared with allogeneic transplantation still needs to be determined. It is conceivable that further improvement can be made if the most effective chemotherapy is combined with a new generation of tyrosine kinase inhibitors and if transplantation in special subgroups is guided by minimal residual disease level.50-52
Modifications of chemotherapy have reduced the rate of recurrence among patients with high-risk ALL but have not yet been shown to improve the outcomes in patients with induction failure.53
Several studies have shown that matched-donor transplantation improved the outcomes in patients with induction failure,23,24,35,54
but the number of patients in each of these studies was too small to determine which patient subgroups had the greatest benefit from transplantation.
Our retrospective analysis has the advantage of including large numbers of patients but is limited by the heterogeneity of the protocols guiding the patients’ treatment. Thus, unmeasured variables could influence the findings. However, our data suggest that allogeneic transplantation may be associated with improved outcomes in patients with T-cell ALL who have not had a complete remission with induction chemotherapy. This observation is consistent with prior reports of improved outcomes in patients with high-risk T-cell ALL receiving transplantation after the first remission.55,56
The number of patients with MLL
rearrangement in whom induction therapy failed is too small in our study to allow us to determine the role of allogeneic transplantation in this subgroup. Allogeneic transplantation failed to improve the outcome in patients with 11q23–MLL
rearrangement in a previous large study from our intergroup collaboration26
but showed some benefits in high-risk subgroups of infants younger than 1 year of age with MLL
rearrangement in the Interfant-99 study (ClinicalTrials.gov number, NCT00015873).57
Finally, our analysis showed no benefit of allogeneic transplantation in patients younger than 6 years of age who had precursor B-cell ALL and induction failure and no high-risk cytogenetic features — an observation with considerable clinical implications, since transplantation is generally considered to be the standard of care for such patients.