Outcomes in childhood acute lymphocytic leukemia (ALL) have steadily improved, in part due to refinements in risk stratification. While several studies have demonstrated the outcome benefits of treatment intensification for children with high-risk features, there have been less frequent examples of successful therapy reduction, perhaps due to hesitation and concern that reductions in treatment intensity could jeopardize the excellent outcomes that are now observed among favorable-risk patients.
Dr. Rob Pieters and colleagues have reported their findings from the ALL10 study in which an essential element of risk stratification was polymerase chain reaction (PCR) –based minimal residual disease (MRD) responses. This study was conducted by the Dutch Childhood Oncology Group (DCOG) from 2004 to 2012 and included 778 patients, aged one to 18 years. Patients were assigned to one of three risk groups based on clinical and biological features of their disease in conjunction with their MRD responses at the end of the first course (day 33; time point 1) and at the end of the second course of therapy (day 79; time point 2). Standard-risk patients comprised approximately 25 percent of the population, and in addition to favorable clinical features, these patients were MRD negative (at least one MRD-PCR target with a quantitative range of 10-4 and one MRD-PCR target with a quantitative range of 5 × 10-4 and sensitivity of 10-4) at time points 1 and 2. High-risk patients (roughly 10%) were defined as: 1) those with poor responses to an initial week of prednisone and IT MTX (prednisone prophase); 2) induction failures; 3) high-risk genetics; or 4) MRD positivity at time point 2. The remaining patients (63% of the population) were medium risk.
In comparison to prior DCOG studies, the intensity of treatment was reduced substantially for standard risk patients. After receiving a four-drug induction, BFM consolidation and high dose methotrexate (courses IA, IB and M) during the first five months of treatment, the intensification and maintenance phases were modified considerably to eliminate additional exposures to cyclophosphamide, cytarabine, 6-thioguanine, and anthracyclines. Furthermore, vincristine and dexamethasone pulses were eliminated altogether during the maintenance phase of treatment, and a total of nine triple intrathecal treatments were delivered, which is a marked reduction from other contemporary childhood ALL protocols. The duration of therapy was two years for both boys and girls. While therapy was reduced for standard-risk patients, treatment was selectively intensified for medium- and high-risk patients. Intensification for medium-risk patients included PEG-asparaginase for 15 weeks and dexamethasone and vincristine pulses following Dana-Farber Cancer Institute regimens, while high-risk patients received six courses of intensive therapy according to the Australian and New Zealand Children’s Haematology/Oncology Group, and some underwent allogeneic stem cell transplantation.
Outcomes for standard-risk patients on this trial were excellent and noninferior to historical trials using more intensive treatment. The five-year event-free survival (EFS) rate was 93.1 percent, the five-year OS rate was 99 percent, and the five-year cumulative incidence of relapse was 6.4 percent, with a central nervous system relapse rate of only 1 percent. The majority (80%) of relapses occurred late with very good chances for salvage. Far fewer grade III/IV toxicities were also observed in comparison to the higher-risk regimens.
Intensification of therapy based on MRD response was also a successful strategy for medium- and high-risk patients, and improvements in EFS compared to historical controls were observed for both of these groups (medium-risk: 5-year EFS, 88% vs. 76%, p=.056; high-risk: 5-year EFS, 78% vs. 16%, p<.001). T-cell ALL outcomes also improved on this trial compared to historical controls; however, many patients were allocated to the high-risk group, and the reduction in relapse rates was counterbalanced by an increase in toxic deaths and secondary malignancies such that EFS and OS remained inferior to B-lineage disease. Similar to the experience of other groups, children with Down syndrome and ALL had inferior outcomes compared to children without Down syndrome due to a combination of excessive deaths from toxicity and higher rates of relapse.
In Brief
Successive improvements in ALL outcomes have afforded an opportunity to evaluate therapy reduction in carefully defined good-risk subsets. MRD response at early time points in treatment has been shown to be the strongest predictor of outcome and when used in combination with clinical features has defined subgroups of patients with survival rates now approaching 100 percent. The results of this study have demonstrated that therapy can be markedly reduced in up to 25 percent of patients and will pave the way for selected treatment reduction in the future, minimizing the burden of ALL treatment for many children, while maintaining excellent chances for a cure.
Competing Interests
Dr. Raetz indicated no relevant conflicts of interest.
