Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG)

Abstract

The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) joined to form the Children's Oncology Group (COG) in 2000. This merger allowed analysis of clinical, biologic, and early response data predictive of event-free survival (EFS) in acute lymphoblastic leukemia (ALL) to develop a new classification system and treatment algorithm. From 11 779 children (age, 1 to 21.99 years) with newly diagnosed B-precursor ALL consecutively enrolled by the CCG (December 1988 to August 1995, n=4986) and POG (January 1986 to November 1999, n=6793), we retrospectively analyzed 6238 patients (CCG, 1182; POG, 5056) with informative cytogenetic data. Four risk groups were defined as very high risk (VHR; 5-year EFS, 45% or below), lower risk (5-year EFS, at least 85%), and standard and high risk (those remaining in the respective National Cancer Institute [NCI] risk groups). VHR criteria included extreme hypodiploidy (fewer than 44 chromosomes), t(9;22) and/or BCR/ABL, and induction failure. Lower-risk patients were NCI standard risk with either t(12;21) (TEL/AML1) or simultaneous trisomies of chromosomes 4, 10, and 17. Even with treatment differences, there was high concordance between the CCG and POG analyses. The COG risk classification scheme is being used for division of B-precursor ALL into lower- (27%), standard- (32%), high- (37%), and very-high- (4%) risk groups based on age, white blood cell (WBC) count, cytogenetics, day-14 marrow response, and end induction minimal residual disease (MRD) by flow cytometry in COG trials.

Figure 1

ALL risk assignment algorithm. Algorithm is for analysis of POG and CCG data. The figure shows the number of evaluable patients in each of the analyses performed. Because the POG had a central immunophenotyping and molecular laboratory system and the CCG relied on peripheral laboratory results, the attrition of evaluable patients in the POG analysis was much lower.

Figure 2

Risk assignment algorithms. Each of the algorithms shows the criteria for placement of patients in (A) standard-risk, (B) high-risk, and (C) very-high-risk assignment. Very-high-risk assignment occurs independently of initial NCI risk assignment (standard or high risk). Patients who have received less than 48 hours of oral or intravenous steroids during the week immediately prior to diagnosis are eligible for classification if the results of a complete blood count (CBC), obtained prior to the initiation of steroid therapy (less than 72 hours prior to steroids), are available and the necessary FISH, cytogenetic, and molecular data are interpretable. The “presteroid” CBC and age of the patient are used to determine NCI-Rome risk classification (standard risk versus high risk [SR versus HR]). If patients have received more than 48 hours of oral or intravenous steroids (and a presteroid CBC is available to assign NCI risk group), they are treated as an SER and nonrandomly assigned to the augmented regimen. In the absence of a presteroid CBC, patients who have received less than 48 hours of steroids are assigned to the HR protocol. These patients are eligible for randomization on the HR protocol. As expected, patients with a slow early response will be assigned to the full augmented BFM treatment arm. In the absence of a presteroid CBC, patients who have received more than 48 hours of steroids are treated as an SER on the HR study and assigned to the full augmented arm. Inhalational steroids are not considered as pretreatment. Both SR and HR patients with identified MLL translocations, CNS-3, or testicular disease, receive augmented SR therapy.

Figure 3

Outcome after classification by the COG risk classification algorithm. (A) CCG 1950s/1960s B-precursor ALL event-free survival outcome by COG risk classification algorithm. The P value for the log-rank test was less than .001. Hazard ratios (with low risk being the baseline) were 1.53 for standard risk, 2.73 for high risk, and 8.82 for very high risk. (B) POG ALinC 16 B-precursor ALL event-free survival outcome by COG risk classification algorithm (does not include rapidity of response because those data were not collected for these studies). The P value for the log-rank test was less than .001. Hazard ratios (with the low-risk group being the baseline) were 2.05 for standard risk, 3.34 for high risk, and 15.02 for very high risk.