Eliminating a gold standard in childhood acute lymphoblastic leukemia?

The dramatic improvement in the cure rates for childhood acute lymphoblastic leukemia (ALL) ranks as one of themost impressive achievements in the campaign against human cancer. With cure rates now approaching 80%, clinicians are faced with new challenges [1,2]. First the prognosis for the 20% of children who fail therapy is poor, and new agents are needed urgently. Additionally, conventional chemotherapy, although curative, is associated with many side effects. Breakthroughs in basic science, particularly in the fields of molecular biology and genomics, have provided a better understanding of the corrupted biological pathways that drive tumor cell progression. A new generation of drugs and biologicals that target these pathways are now being developed and it is likely that many of these agents will replace or augment cytotoxic chemotherapy in the future. How should investigators prioritize among the many compounds that industry is now providing and how can they enter the clinical arena quickly so that they can benefit the patients who need them? Although randomized studies are the hallmark of research in pediatric oncology and have led to many of the advances seen today, they routinely take many years to complete and analyze. Given the high cure rate of childhood ALL, it is not uncommon for a study to take a decade from study design before the final results are known. While pre-clinical work and Phase I/II trials might help to prioritize new agents for evaluation, such promising compounds very often do not result in improved survival for children in the frontline setting. Investing in the ‘‘wrong’’ agent while the ‘‘right’’ one remains on the shelf leads to the loss of valuable time. Given these issues, can ALL investigators afford to continue to rely exclusively upon randomized studies that use event-free survival (EFS) as the primary endpoint? Early response to treatment has been shown to be one of the most important prognostic factors in childhood ALL. Traditionally, this has been determined by morphological assessment of blast clearance during induction, either by examining regression of peripheral blood or bone marrow blasts. Virtually all studies have shown that rapid blast regression is associated with superior EFS and this variable has been used in recent years to stratify patients [3–5]. In fact early augmentation of therapy for patients who demonstrate slow clearance of blasts has led to improved outcomes [6]. More sensitive techniques to measure disease regression have now been developed to supplement or replace traditional morphological assessments. Namely, using either PCR-based or flow-cytometry-based strategies, minimal residual disease (MRD) can be detected with a sensitivity of at least 10 . Regardless of the technique used, the persistence of MRD at early time points during therapy consistently has been shown to correlate with inferior outcomes for children with both newly diagnosed and recurrent ALL [7–11]. MRD measurements are currently being used in parallel with morphological assessment of disease regression to tailor post-induction therapy for children and young adults with newly diagnosed ALL. Can early response measurements also be used to determine the effectiveness of therapeutic interventions? The article by Yeoh and colleagues [12] in this issue of Pediatric Blood and Cancer addresses this issue. These investigators have used MRD as a tool to compare the effectiveness of two different preparations of asparaginase during induction. The authors measured MRD at the end of induction therapy courses in which either Escherichia coli (E. coli) or Erwinia chrysanthemi asparaginase were given. They demonstrated a lesser end induction disease burden in the recipients of E. coli asparaginase, which importantly was also associated with more favorable disease-free survival (DFS) rates in this group. Due to small patient numbers, comparisons ofDFS in theMRD-positiveE. coli andErwinia asparaginase patients were not made separately. The outcome of this study is not surprising since other studies have reported the superiority of E. coli over Erwinia preparations previously [13]. The study by Yeoh and colleagues was not randomized and no attempt was made to adjust schedules to account for the shorter half-life of Erwinia asparaginase. However, this report demonstrates the feasibility of using early assessment of MRD to assess the effectiveness of particular agents, and also demonstrated that this was a