Early intensification of treatment with postinduction myeloid-type chemotherapy did not improve outcomes compared with standard lymphoid-type chemotherapy in infants with acute lymphoblastic leukemia (ALL), according to the results of a study testing the Interfant-06 protocol published in Journal of Clinical Oncology.
The large international study pooled patients from 18 national and international study groups. It included 651 infants with ALL who were divided into three risk groups: low risk (KMT2A germline), high-risk (KMT2A-rearranged and older than 6 months with white blood cell count 300 x 109/L or more or a poor prednisone response), and medium-risk (all other KMT2A-rearranged cases).
Those patients considered high- or medium-risk were randomly assigned to a lymphoid course of therapy, IB (low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide), or experimental myeloid courses. Myeloid courses included araC, daunorubicin, etoposide (ADE), and mitoxantrone, araC, etoposide (MAE).
“The randomized use of two intensive myeloid-like chemotherapy courses did not lead to a statistically better outcome than the classic lymphoid-like course IB,” Rob Pieters, MD, of Dutch Childhood Oncology Group, and colleagues wrote in Journal of Clinical Oncology. “Our study shows that infant patients with ALL do not benefit from early intensification of therapy with additional araC and daunorubicin, or from the other drugs, mitoxantrone and etoposide, as given in these AML-like courses.”
Overall, 6-year event-free survival was 46.1% and overall survival was 58.2%. Among the West European/North American groups, 6-year event-free survival was 49.4% and overall survival was 62.1%. Overall survival was 12% higher in this group that that of other countries “mainly because of fewer toxic deaths, illustrating how regional handling on this protocol influences outcome”.
Patients assigned to ADE+MAE had a 6-year event-free survival of 39.3%, comparable to the 36.8% 6-year event-free survival seen in patients assigned to IB.
Commenting on the study, William L. Carroll, MD, of New York University’s Stephen D. Hassenfeld Children's Center for Cancer and Blood Disorders in New York City, said that unlike childhood ALL, where children have 90% survival rates, infants with ALL tend to do poorly because the majority of them have KMT2A rearrangement, which portends a poor prognosis.
“These cases are characterized with lymphoid markers, but many aspects of the underlying biology also indicate myeloid characteristics,” Carroll said. “For a long time, people debated if kids should be treated with AML therapy.”
This negative study should put an end to that debate, Carroll said. It also had important findings related to prognostic subgroups. According to the researchers, KMT2A rearrangement was the strongest prognostic factors for event-free survival. In addition, younger age at diagnosis was associated with inferior outcomes, as was white blood cell count of 300 x 109/L or greater. KMT2A germline patients and those with lower white counts had better outcomes.
“That should set the stage for additional studies of these prognostic elements,” Carroll said.
In addition, the negative results suggest that trials investigating dosing of conventional chemotherapy or dose intensification should not continue. Instead, immunotherapy should be the next step to investigating this rare disease, Carroll said.
“This is a good study and a negative study,” Carroll said. “Negative studies don’t often get as much publicity, but often provide the direction for the next breakthrough.”