Continue to study childhood ALL

To the editor:

In Inside Blood's provocatively titled “ ‘Lesser’ ALL: treat less or study less?,”¹  Dr Feusner questions whether, “in the current age of declining funding for research, is it worth it to study a disease in which at least 95% of the patients would be expected to survive, regardless of treatment regimen assigned?” This question arose in the context of the dueling favorable reports from legacy Children's Cancer Group (CCG)²  and Pediatric Oncology Group (POG) trials,³  as well as outstanding results from acute lymphoblastic leukemia (ALL) treatment groups at St. Jude and elsewhere.⁴ 

For several reasons, we argue that it is still necessary to conduct clinical trials in patients with so-called lesser-risk ALL. First, treatment still needs to be improved in this subgroup of patients. In the POG trial, the 6-year event-free survival rate was 86.6% (± 1.8%; SE) and in the best arm of the CCG study with the use of dexamethasone and oral mercaptopurine, the 6-year event-free survival rate was also 86% (± 2%). It is also recognized that late recurrence, albeit uncommon, could still occur well beyond 6 years from remission induction.⁵  Hence, 15% or more of the patients from either study would require retrieval therapy for relapsed leukemia and likely encounter treatment-related complications. Second, the optimal treatment for cure in this group of patients has yet to be determined. The POG trial featured 6 courses of high-dose methotrexate and 8 pulses of glucocorticoid and vincristine after remission induction, whereas the CCG trial incorporated a delayed intensification phase with 8 drugs, including asparaginase, cyclophosphamide, and doxorubicin, and 32 pulses of glucocorticoid and vincristine after remission induction. Conceivably, incorporation of high-dose methotrexate and delayed intensification into the backbone of either trial could further improve the outcome. However, clinical trials are still needed to determine the optimal doses and courses of high-dose methotrexate, and glucocorticoid and vincristine pulses, as well as the extent of the delayed intensification.

Third, a critical function of phase 3 trials is not only to identify the better regimen, but also to provide the clinical trial platforms in which biological and genomic studies can be performed so that the host- and treatment-related determinants of acute and late adverse events (including relapse, second cancer, hospitalization rates, and long-term consequences) can be defined. These studies are essential to optimize treatment (ie, lower toxicities while increasing efficacy) with already-approved drugs and therapies, but require systematic assessment of a large number of patients treated uniformly (ie, on protocols).

National Cancer Institute (NCI)–sponsored phase 3 clinical trials play a critical role in translational research, even in “lesser” risk ALL and in the absence of any randomized treatment question. For example, it will be impossible to use the genomic variation that has been defined by the Human Genome and HapMap projects to improve therapy without conducting translational research in the context of standardized treatment. In this regard, clinical databases and the collection of basic biological material (eg, one blood sample per patient for genomic DNA) should be a standard component of contemporary cancer clinical trials. As has been demonstrated in some adult diseases with much lower mortality rates than cancer,⁶  we must have multiple trials enrolling hundreds to thousands of patients to confidently identify genomic variants that are suitable for tailoring therapy.

We agree that creative funding strategies may be needed to support trials in the coming years so that translational research can move forward. Nevertheless, we hope that an acceptable option won't be to “study less” childhood ALL. If, over the past 40 years, pediatric cancer trial participation throughout the US had averaged the 40% refusal rate that Dr Feusner has reported for standard-risk ALL, we suspect we would not be anguishing over what steps to take now that cure rates approach 90% in this disease.