LETTER TO THE EDITOR Reply to "Peripheral Blood Lymphocyte Recovery and Overall Survival in Pediatric Acute Lymphoblastic Leukemia"

To the Editor: Hatzipantelis et al. report on the prognostic impact of absolute lymphocyte count (ALC) recovery at day þ29 after induction chemotherapy in a retrospective study of 117 childrentreatedwiththeBFM/ALLIC2009chemotherapyprotocol attheirinstitutioninGreece.Theyfoundthatacut-offvalueofALC � 350cells/ml was associated with a significantly more favorable prognosis (5-year OS 92.3% vs. 69.2%, HR 2.2, P ¼0.05), providing further evidence of the association between high ALC and improved outcome that has been previously demonstrated in pediatric ALL, as well as numerous other adult and pediatric malignancies. In assessing their review of the literature on the prognostic significance of ALC (Table I), it is important to consider that the exact numeric ALC cutoff that is most predictive of prognosis would be expected to differ depending on the induction treatment regimen. Moreover, the optimal time point at which to assess ALC recovery will differ depending on the intensity of the induction regimenandhencethekineticsofmarrowrecovery.Thespecificsof the induction regimen in the study by Hatzipantelis et al. are not referenced in their communication, but differences from the regimens used in our prior studies likely account for the differences they observed in both the ALC cutoff (350 vs. 1,500cells/ml [1]) and the time point (induction day 29 vs. day 15 [2]) that were predictive of outcome. Similarly, treatment differences likely account for the lack of independent prognostic significance of ALC in recent reports by Alkayed et al. [3] and Rubnitz et al. [4]. The modified St. Judeinduction regimen used in Ref. [3] included seven drugs, with ALC assessment at day 36. The St. Jude Total XV induction regimen used in Ref. [4] included eight drugs, with modification (three extra doses of L-asparaginase) during induction based on early bone marrow response at day 19. While the prognostic significance of specific ALC numeric cutoffs and measurement time points may differ somewhat across studies, we and others believe that the bulk of evidence in ALL and other malignancies affirms that early ALC recovery is a useful and independent marker of favorable prognosis [2,5‐7]. It appears that timingandcutoffsforlymphocytecountswill needtobedefined for different treatment regimens and different patient populations. To thisend,theChildren’sOncologyGroupisprospectivelyevaluating ALCatday29ofafour-druginductiononthecurrenthighriskALL study AALL1131. In addition to its potential role in the context of MRD-based risk stratification, we also note that ALC has particular potential as a clinical tool contributing to risk stratification in developing countries. Many of these countries use a standard threeor four-drug induction regimen such as those studied in our prior report [1], and do not have access to MRD analysis to guide risk stratification. Use of ALC as a proxy for MRD assessment (when MRD is not available) may improve ALL outcomes in developing countries by identifying those patients who would benefit from a more intensive treatment regimen.